G3946A

# **General Information**

| **Position** | **3946** | **Variant** | **m.3946G\>A** | **Locus** | **MT\-ND1** | **Amino\-AcidChange** | **E214K** |
| --- | --- | --- | --- | --- | --- | --- | --- |
| **Homoplasmy** | \+ | **Heteroplasmy** | \+ | **APOGEE2** | Likely\-pathogenic | **Pathogenicity** | Cfrm \[LP] |

"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.3946G\>A** variant in MT\-ND1 has been reported in 4 pedigrees. To date, 6 carriers have been reported. Reported mutation loads ranged from 0% to 77%, with a median of 48% overall; affected carriers showed mutation loads from 27\.5% to 77%, with a median of 60%; unaffected carriers showed mutation loads from 0% to 3%, with a median of 0%. In one affected carrier, a marked tissue\-specific difference was observed, with higher mutation loads in muscle (77%) than in blood (27\.5%). The main clinical manifestations among affected carriers included MELAS, iV defect, infantile spasms, leigh syndrome with complex I, cortical visual impairment, and severe neurodevelopmental disorder.

| **No.** | **Position** | **Variant** | **Family ID** | **Nationality** | **Diseases** | **Unaffected Maternal Relatives** | **Affected Maternal Relatives** | **Publication Year** | **PMID/Ref** | **Note** |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| 1 | 3946 | m.3946G\>A | G3946A\-F1 | Australia | MELAS | 2 | 0 | 2004 | [15466014](https://pubmed.ncbi.nlm.nih.gov/15466014/) |  |
| 2 | 3946 | m.3946G\>A | G3946A\-F2 | Japan | Leigh syndrome | 0 | 0 | 2017 | [28429146](https://pubmed.ncbi.nlm.nih.gov/28429146/) |  |
| 3 | 3946 | m.3946G\>A | G3946A\-F3 | USA | MELAS | 0 | 0 | 2022 | [34969639](https://pubmed.ncbi.nlm.nih.gov/34969639/) |  |
| 4 | 3946 | m.3946G\>A | G3946A\-F4 | USA | Infantile spasms / severe neurodevelopmental disorder | 0 | 0 | 2025 | [40241304](https://pubmed.ncbi.nlm.nih.gov/40241304/) |  |

# **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 | 3946 | m.3946G\>A | G3946A\-F1 | G3946A\-F1\-I2 | Uninf | F | N | N | A | ND | 0 | / | 0 | / | healthy |  |
| 2 | 3946 | m.3946G\>A | G3946A\-F1 | G3946A\-F1\-II1 | Fam | F | Y | Y | A | 14 | 37% | 60% | / | 45% (F) | MELAS |  |
| 3 | 3946 | m.3946G\>A | G3946A\-F1 | G3946A\-F1\-II2 | Fam | F | N | N | A | ND | / | / | 3% | / | healthy |  |
| 4 | 3946 | m.3946G\>A | G3946A\-F2 | G3946A\-F2\-I1 | Uninf | ND | Y | Y | A | ND | / | 66% | / | / | Leigh syndrome with complex I/IV defect |  |
| 5 | 3946 | m.3946G\>A | G3946A\-F3 | G3946A\-F3\-I1 | De novo | ND | Y | Y | A | 16 | 27\.5% | 77% | / | 51% (saliva) | MELAS | Mother blood and saliva undetected. |
| 6 | 3946 | m.3946G\>A | G3946A\-F4 | G3946A\-F4\-I1 | Uninf | ND | Y | Y | A | ND | / | / | / | 70% (ES); 68% (RNA\-seq) | Infantile spasms, cortical visual impairment, severe neurodevelopmental disorder |  |

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