A8296G

# **General Information**

| **Position** | **8296** | **Variant** | **m.8296A\>G** | **Locus** | **MT\-TK** | **RNA** | **tRNA Lys** |
| --- | --- | --- | --- | --- | --- | --- | --- |
| **Homoplasmy** | \+ | **Heteroplasmy** | \+ | **mitoTIP** | 72\.30% | **Pathogenicity** | Reported \[VUS] |

"Pathogenicity" status is derived from published literature or predictions from bioinformatics tools. Researchers and clinicians are cautioned that additional data and/or analysis may still be necessary to confirm the pathological significance of these variants. For more information, please see [Mitofam Info](https://mitofam.com/doc/385/).

# **Pedigree Information**

The **m.8296A\>G** variant in MT\-TK has been reported in 30 pedigrees. To date, 46 carriers have been reported. Homoplasmy was reported in 1/46 carriers (2\.2%), and 44/46 carriers (95\.7%) were affected. The main clinical manifestations among affected carriers included diabetes mellitus, impaired insulin secretion, NIDDM, no hearing loss, IDDM, hearing loss, hyperinsulinemia, 75 dB, and other features.

| **No.** | **Position** | **Variant** | **Family ID** | **Nationality** | **Diseases** | **Unaffected Maternal Relatives** | **Affected Maternal Relatives** | **Publication Year** | **PMID/Ref** | **Note** |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 1 | 8296 | m.8296A\>G | A8296G\-F1 | Japan | Diabetes mellitus; hearing loss | 0 | 0 | 1998 | [9571188](https://pubmed.ncbi.nlm.nih.gov/9571188/) | / |
| 2 | 8296 | m.8296A\>G | A8296G\-F2 | Japan | Diabetes mellitus | 0 | 0 | 1998 | [9571188](https://pubmed.ncbi.nlm.nih.gov/9571188/) | / |
| 3 | 8296 | m.8296A\>G | A8296G\-F3 | Japan | Diabetes mellitus | 0 | 0 | 1998 | [9571188](https://pubmed.ncbi.nlm.nih.gov/9571188/) | / |
| 4 | 8296 | m.8296A\>G | A8296G\-F4 | Japan | Diabetes mellitus | 0 | 0 | 1998 | [9571188](https://pubmed.ncbi.nlm.nih.gov/9571188/) | / |
| 5 | 8296 | m.8296A\>G | A8296G\-F5 | Japan | Diabetes mellitus | 0 | 0 | 1998 | [9571188](https://pubmed.ncbi.nlm.nih.gov/9571188/) | / |
| 6 | 8296 | m.8296A\>G | A8296G\-F6 | Japan | Diabetes mellitus; hearing loss | 0 | 0 | 1998 | [9571188](https://pubmed.ncbi.nlm.nih.gov/9571188/) | / |
| 7 | 8296 | m.8296A\>G | A8296G\-F7 | Japan | Diabetes mellitus | 0 | 0 | 1998 | [9571188](https://pubmed.ncbi.nlm.nih.gov/9571188/) | / |
| 8 | 8296 | m.8296A\>G | A8296G\-F8 | Japan | Diabetes mellitus | 0 | 0 | 1998 | [9571188](https://pubmed.ncbi.nlm.nih.gov/9571188/) | / |
| 9 | 8296 | m.8296A\>G | A8296G\-F9 | Japan | Diabetes mellitus | 0 | 0 | 1998 | [9571188](https://pubmed.ncbi.nlm.nih.gov/9571188/) | / |
| 10 | 8296 | m.8296A\>G | A8296G\-F10 | Japan | Diabetes mellitus | 0 | 0 | 1998 | [9571188](https://pubmed.ncbi.nlm.nih.gov/9571188/) | / |
| 11 | 8296 | m.8296A\>G | A8296G\-F11 | Japan | Diabetes mellitus | 0 | 0 | 1998 | [9571188](https://pubmed.ncbi.nlm.nih.gov/9571188/) | / |
| 12 | 8296 | m.8296A\>G | A8296G\-F12 | Japan | Hearing loss; diabetes mellitus | 0 | 0 | 1998 | [9571188](https://pubmed.ncbi.nlm.nih.gov/9571188/) | / |
| 13 | 8296 | m.8296A\>G | A8296G\-F13 | Japan | Diabetes mellitus; impaired insulin secretion | 0 | 0 | 1998 | [9802769](https://pubmed.ncbi.nlm.nih.gov/9802769/) | Family DM1 |
| 14 | 8296 | m.8296A\>G | [A8296G\-F14](https://mitofam.com/doc/2168/) | Japan | Diabetes mellitus; impaired insulin secretion | 0 | 0 | 1998 | [9802769](https://pubmed.ncbi.nlm.nih.gov/9802769/) | Family DM2 |
| 15 | 8296 | m.8296A\>G | A8296G\-F15 | Japan | Diabetes mellitus; impaired insulin secretion | 0 | 0 | 1998 | [9802769](https://pubmed.ncbi.nlm.nih.gov/9802769/) | Family DM3 |
| 16 | 8296 | m.8296A\>G | A8296G\-F16 | Japan | Diabetes mellitus; impaired insulin secretion | 0 | 0 | 1998 | [9802769](https://pubmed.ncbi.nlm.nih.gov/9802769/) | Family DM4 |
| 17 | 8296 | m.8296A\>G | A8296G\-F17 | Japan | Diabetes mellitus; hyperinsulinemia | 0 | 0 | 1998 | [9802769](https://pubmed.ncbi.nlm.nih.gov/9802769/) | Family DM5 |
| 18 | 8296 | m.8296A\>G | A8296G\-F18 | Japan | Diabetes mellitus; impaired insulin secretion | 0 | 0 | 1998 | [9802769](https://pubmed.ncbi.nlm.nih.gov/9802769/) | Family DM6 |
| 19 | 8296 | m.8296A\>G | [A8296G\-F19](https://mitofam.com/doc/2169/) | Japan | Diabetes mellitus; impaired insulin secretion | 0 | 0 | 1998 | [9802769](https://pubmed.ncbi.nlm.nih.gov/9802769/) | Family DM7 |
| 20 | 8296 | m.8296A\>G |[ A8296G\-F20](https://mitofam.com/doc/2170/) | Japan | Diabetes mellitus; impaired insulin secretion | 0 | 0 | 1998 | [9802769](https://pubmed.ncbi.nlm.nih.gov/9802769/) | Family DM8 |
| 21 | 8296 | m.8296A\>G | A8296G\-F21 | Japan | Diabetes mellitus; impaired insulin secretion | 0 | 0 | 1998 | [9802769](https://pubmed.ncbi.nlm.nih.gov/9802769/) | Family DM9 |
| 22 | 8296 | m.8296A\>G | [A8296G\-F22](https://mitofam.com/doc/2171/) | Japan | Diabetes mellitus; impaired insulin secretion | 0 | 0 | 1998 | [9802769](https://pubmed.ncbi.nlm.nih.gov/9802769/) | Family DM10 |
| 23 | 8296 | m.8296A\>G | [A8296G\-F23](https://mitofam.com/doc/2172/) | Japan | Diabetes mellitus; impaired insulin secretion | 0 | 0 | 1998 | [9802769](https://pubmed.ncbi.nlm.nih.gov/9802769/) | Family DM11 |
| 24 | 8296 | m.8296A\>G | [A8296G\-F24](https://mitofam.com/doc/2173/) | Japan | Diabetes mellitus; hyperinsulinemia | 0 | 0 | 1998 | [9802769](https://pubmed.ncbi.nlm.nih.gov/9802769/) | Family DM12 |
| 25 | 8296 | m.8296A\>G | [A8296G\-F25](https://mitofam.com/doc/2174/) | Japan | Fatal hypertrophic obstructive cardiomyopathy / mitochondrial cardiomyopathy | 2 | 0 | 2000 | [10737988](https://pubmed.ncbi.nlm.nih.gov/10737988/) | / |
| 26 | 8296 | m.8296A\>G | A8296G\-F26 | Finland | Occipital stroke; migraine | 0 | 0 | 2001 | [11406419](https://pubmed.ncbi.nlm.nih.gov/11406419/) | / |
| 27 | 8296 | m.8296A\>G | A8296G\-F27 | Japan | Atypical MELAS | 0 | 0 | 2002 | [12504210](https://pubmed.ncbi.nlm.nih.gov/12504210/) | / |
| 28 | 8296 | m.8296A\>G | [A8296G\-F28](https://mitofam.com/doc/2175/) | India | Type 2 diabetes mellitus | 0 | 1 | 2010 | [20143911](https://pubmed.ncbi.nlm.nih.gov/20143911/) | / |
| 29 | 8296 | m.8296A\>G | A8296G\-F29 | Chinese | Non\-syndromic hearing loss | 0 | 0 | 2020 | [32169613](https://pubmed.ncbi.nlm.nih.gov/32169613/) | Table 2 proband MTD075 |
| 30 | 8296 | m.8296A\>G | A8296G\-F30 | Japan | Sensorineural hearing loss | 0 | 0 | 2024 | [37573175](https://pubmed.ncbi.nlm.nih.gov/37573175/) | Fig. 1 family tree |

# **Carrier Information**

| **No.** | **Position** | **Variant** | **Family ID** | **Carrier ID** | **Type (Fam/De novo/Uninf)** | **Gender (F/M)** | **Proband (Y/N)** | **Affected (Y/N)** | **Die/Alive(D/A)** | **Age** | **Blood Mutant Level** | **Muscle Mutant level** | **Urine Mutant level** | **Other Mutant level** | **Clinical Features** | **Note** |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 1 | 8296 | m.8296A\>G | A8296G\-F1 | A8296G\-F1\-P1 | Fam | ND | Y | Y | A | 40 | Hetero; load NR | / | / | / | NIDDM; hearing loss | Original label: DM1; peripheral leukocyte heteroplasmy, load NR; deafness by conventional conversation. |
| 2 | 8296 | m.8296A\>G | A8296G\-F2 | A8296G\-F2\-P1 | Fam | ND | Y | Y | A | 43 | Hetero; load NR | / | / | / | NIDDM | Original label: DM2; peripheral leukocyte heteroplasmy, load NR; deafness by audiometer. |
| 3 | 8296 | m.8296A\>G | A8296G\-F3 | A8296G\-F3\-P1 | Fam | ND | Y | Y | A | 41 | Hetero; load NR | / | / | / | NIDDM; no hearing loss | Original label: DM3; peripheral leukocyte heteroplasmy, load NR; deafness not detected by audiometer. |
| 4 | 8296 | m.8296A\>G | A8296G\-F4 | A8296G\-F4\-P1 | Uninf | ND | Y | Y | A | 60 | Hetero; load NR | / | / | / | NIDDM | Original label: DM4; peripheral leukocyte heteroplasmy, load NR; deafness not determined. |
| 5 | 8296 | m.8296A\>G | A8296G\-F5 | A8296G\-F5\-P1 | Uninf | ND | Y | Y | A | 47 | Hetero; load NR | / | / | / | NIDDM | Original label: DM5; peripheral leukocyte heteroplasmy, load NR; deafness by audiometer. |
| 6 | 8296 | m.8296A\>G | A8296G\-F6 | A8296G\-F6\-P1 | Fam | ND | Y | Y | A | 61 | Hetero; load NR | / | / | / | NIDDM; hearing loss | Original label: DM6; peripheral leukocyte heteroplasmy, load NR; deafness by conventional conversation. |
| 7 | 8296 | m.8296A\>G | A8296G\-F7 | A8296G\-F7\-P1 | Fam | ND | Y | Y | A | 54 | Hetero; load NR | / | / | / | NIDDM | Original label: DM7; peripheral leukocyte heteroplasmy, load NR; deafness by audiometer. |
| 8 | 8296 | m.8296A\>G | A8296G\-F8 | A8296G\-F8\-P1 | Fam | ND | Y | Y | A | 35 | Hetero; load NR | / | / | / | NIDDM; no hearing loss | Original label: DM8; peripheral leukocyte heteroplasmy, load NR; deafness not detected by audiometer. |
| 9 | 8296 | m.8296A\>G | A8296G\-F9 | A8296G\-F9\-P1 | Uninf | ND | Y | Y | A | 44 | Hetero; load NR | / | / | / | NIDDM; no hearing loss | Original label: DM9; peripheral leukocyte heteroplasmy, load NR; deafness not detected by audiometer. |
| 10 | 8296 | m.8296A\>G | A8296G\-F10 | A8296G\-F10\-P1 | Fam | ND | Y | Y | A | 31 | Hetero; load NR | / | / | / | IDDM; no hearing loss | Original label: DM10; peripheral leukocyte heteroplasmy, load NR; deafness not detected by audiometer. |
| 11 | 8296 | m.8296A\>G | A8296G\-F11 | A8296G\-F11\-P1 | Fam | ND | Y | Y | A | 45 | Hetero; load NR | / | / | / | IDDM | Original label: DM11; peripheral leukocyte heteroplasmy, load NR; deafness by audiometer. |
| 12 | 8296 | m.8296A\>G | A8296G\-F12 | A8296G\-F12\-P1 | Fam | ND | Y | Y | A | 47 | Hetero; load NR | / | / | / | Hearing loss; NIDDM | Original label: DF1; peripheral leukocyte heteroplasmy, load NR; deafness by conventional conversation; selected from deafness group. |
| 13 | 8296 | m.8296A\>G | A8296G\-F13 | A8296G\-F13\-P1 | Uninf | ND | ND | Y | A | 69 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; individual load not reported. |
| 14 | 8296 | m.8296A\>G | A8296G\-F14 | A8296G\-F14\-II1 | Fam | ND | ND | Y | A | 47 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 15 | 8296 | m.8296A\>G | A8296G\-F14 | A8296G\-F14\-II2 | Fam | ND | ND | Y | A | 63 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 16 | 8296 | m.8296A\>G | A8296G\-F14 | A8296G\-F14\-II3 | Fam | ND | ND | Y | A | 61 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 17 | 8296 | m.8296A\>G | A8296G\-F14 | A8296G\-F14\-II4 | Fam | ND | ND | Y | A | 58 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 18 | 8296 | m.8296A\>G | A8296G\-F14 | A8296G\-F14\-II5 | Fam | ND | ND | Y | A | 55 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 19 | 8296 | m.8296A\>G | A8296G\-F14 | A8296G\-F14\-II6 | Fam | ND | ND | Y | A | 50 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 20 | 8296 | m.8296A\>G | A8296G\-F15 | A8296G\-F15\-P1 | Uninf | ND | ND | Y | A | 57 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; individual load not reported. |
| 21 | 8296 | m.8296A\>G | A8296G\-F16 | A8296G\-F16\-P1 | Uninf | ND | ND | Y | A | 69 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; individual load not reported. |
| 22 | 8296 | m.8296A\>G | A8296G\-F17 | A8296G\-F17\-P1 | Uninf | ND | ND | Y | A | 61 | / | / | / | Hetero (ND) | Diabetes mellitus; hyperinsulinemia | One of two subjects with hyperinsulinemia; load not reported. |
| 23 | 8296 | m.8296A\>G | A8296G\-F18 | A8296G\-F18\-P1 | Uninf | ND | ND | Y | A | 73 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; individual load not reported. |
| 24 | 8296 | m.8296A\>G | A8296G\-F19 | A8296G\-F19\-II1 | Fam | ND | ND | Y | A | 64 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 25 | 8296 | m.8296A\>G | A8296G\-F19 | A8296G\-F19\-II2 | Fam | ND | ND | Y | A | 58 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 26 | 8296 | m.8296A\>G | A8296G\-F20 | A8296G\-F20\-II1 | Fam | ND | ND | Y | A | 46 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 27 | 8296 | m.8296A\>G | A8296G\-F20 | A8296G\-F20\-II2 | Fam | ND | ND | Y | A | 79 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 28 | 8296 | m.8296A\>G | A8296G\-F20 | A8296G\-F20\-II3 | Fam | ND | ND | Y | A | 49 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 29 | 8296 | m.8296A\>G | A8296G\-F20 | A8296G\-F20\-II4 | Fam | ND | ND | Y | A | 40 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 30 | 8296 | m.8296A\>G | A8296G\-F21 | A8296G\-F21\-P1 | Uninf | ND | ND | Y | A | 56 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; individual load not reported. |
| 31 | 8296 | m.8296A\>G | A8296G\-F22 | A8296G\-F22\-II1 | Fam | ND | ND | Y | A | 58 | / | / | / | Hetero (ND) | IDDM; impaired insulin secretion | One of two subjects diagnosed as IDDM; relationship not reported. |
| 32 | 8296 | m.8296A\>G | A8296G\-F22 | A8296G\-F22\-II2 | Fam | ND | ND | Y | A | 50 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 33 | 8296 | m.8296A\>G | A8296G\-F23 | A8296G\-F23\-II1 | Fam | ND | ND | Y | A | 75 | / | / | / | Hetero (ND) | IDDM; impaired insulin secretion | One of two subjects diagnosed as IDDM; relationship not reported. |
| 34 | 8296 | m.8296A\>G | A8296G\-F23 | A8296G\-F23\-II2 | Fam | ND | ND | Y | A | 69 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 35 | 8296 | m.8296A\>G | A8296G\-F23 | A8296G\-F23\-II3 | Fam | ND | ND | Y | A | 45 | / | / | / | Hetero (ND) | Impaired glucose tolerance; impaired insulin secretion | Table 1 subject; onset/treatment OCR is unclear, not entered. |
| 36 | 8296 | m.8296A\>G | A8296G\-F24 | A8296G\-F24\-II1 | Fam | ND | ND | Y | A | 47 | / | / | / | Hetero (ND) | Diabetes mellitus; impaired insulin secretion | Table 1 subject with the 8296 mutation; relationship not reported. |
| 37 | 8296 | m.8296A\>G | A8296G\-F24 | A8296G\-F24\-II2 | Fam | ND | ND | Y | A | 83 | / | / | / | Hetero (ND) | Diabetes mellitus; hyperinsulinemia | One of two subjects with hyperinsulinemia; relationship not reported. |
| 38 | 8296 | m.8296A\>G | A8296G\-F25 | A8296G\-F25\-II1 | Fam | F | Y | Y | D | 8 days | / | 96% | / | 97% (Heart); 97% (Liver); 95% (Spleen); 97% (Pancreas); 95% (Kidney); 97% (Lung); 92% (Brain) | Fatal hypertrophic cardiomyopathy; neonatal tachypnea; hypotonia; muscle weakness; hepatomegaly; cardiomegaly; metabolic acidosis; elevated lactate/pyruvate/ammonia | Autopsy tissue mutation loads from Figure 2\. |
| 39 | 8296 | m.8296A\>G | A8296G\-F25 | A8296G\-F25\-II2 | Fam | F | N | N | A | ND | 93% | / | / | / | Healthy | WBC mutation load from Figure 2/text. |
| 40 | 8296 | m.8296A\>G | A8296G\-F25 | A8296G\-F25\-I1 | uninf | F | N | N | A | ND | 93% | / | / | / | Healthy | WBC mutation load from Figure 2/text. |
| 41 | 8296 | m.8296A\>G | A8296G\-F26 | A8296G\-F26\-P1 | Uninf | F | Y | Y | A | 35 | Homo | / | / | / | Occipital stroke; migraine; visual field defect | Age is onset age. Blood\-derived mtDNA; subclones homoplasmic. Singleton patient 148; no pedigree\-based relatives with target molecular evidence. |
| 42 | 8296 | m.8296A\>G | A8296G\-F27 | A8296G\-F27\-P1 | Uninf | M | Y | Y | A | 14 | / | Hetero | / | / | Atypical MELAS; optic atrophy; hypertrophic cardiomyopathy; SNHL; seizures; lactic acidosis; stroke\-like episodes | Qualitative muscle heteroplasmy by PCR/AciI; no percentage reported. |
| 43 | 8296 | m.8296A\>G | A8296G\-F28 | A8296G\-F28\-II1 | Fam | M | Y | Y | A | 38 | Hetero; load NR | / | / | / | Type 2 diabetes mellitus; onset 34; no hearing loss | Original label: Case 1; m.8296A\>G detected in peripheral leukocyte DNA; no numeric load reported; siblings asymptomatic and untested. |
| 44 | 8296 | m.8296A\>G | A8296G\-F28 | A8296G\-F28\-I1 | uninf | F | N | Y | A | ND | / | / | / | Detected (ND) | Diabetes mellitus; neuromuscular disorder | Original relationship: mother of Case 1; same m.8296A\>G mutation shared; sample/source and numeric load not separately specified. |
| 45 | 8296 | m.8296A\>G | A8296G\-F29 | A8296G\-F29\-P1 | Uninf | F | Y | Y | ND | 2 | / | / | / | / | Severe non\-syndromic hearing loss; PTA 95/75 dB | Proband MTD075; age is age at onset from Table 2; peripheral blood Sanger positive, heteroplasmy not reported; co\-variant MT\-TA m.5587T\>C; haplogroup F1e; family history yes |
| 46 | 8296 | m.8296A\>G | A8296G\-F30 | A8296G\-F30\-III4 | Uninf | F | Y | Y | A | 66 | Hetero; load NR | / | / | / | Progressive severe bilateral sensorineural hearing loss; vestibular dysfunction; no diabetes | Fig. 1 III4/proband; peripheral leukocyte heteroplasmy by gene\-targeted sequencing, load not reported; family members were not genetically tested; underwent cochlear implantation. |

For abbreviations and other usage instructions, please see [Mitofam Info](https://mitofam.com/doc/385/).