Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV005251031 | SCV005901631 | uncertain significance | Mitochondrial disease | 2023-09-11 | reviewed by expert panel | curation | The m.3394T>C (p.Y30H) variant in MT-ND1 has been reported in 157 individuals with phenotypes consistent with primary mitochondrial disease, including Leber Hereditary Optic Neuropathy (LHON) and diabetes. This variant was present in 2.1% of 1,741 individuals in one cohort of LHON, and is thought to increase penetrance and occurrence of optic neuropathy in families when present with the well-known pathogenic variant, m.11778G>A (PMID: 30597069). The m.3394T>C variant is widely considered a secondary "helper" variant, not a variant associated with primary mitochondrial disease. However, of the 157 cases reported to date, the m.3394T>C variant has been reported without an accompanying primary mitochondrial disease-associated variant in 31 LHON families, two individuals with diabetes, and one individual with hypertrophic cardiomyopathy (PS4). Although outside the scope of this curation, this variant also been shown to be adaptive for high-altitude Tibetans where multiple independent origins of m.3394T>C have been documented (PMID: 22517755). The variant is present in 100% in Tibetan-associated haplogroups M9a (349/349) and M9b (4/4) in MITOMAP. In a study of type 2 diabetes mellitus in Han Chinese, this variant was found with significantly higher frequency in affected individuals (23.6%) than in the controls (2.0%; PMID: 18679013). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.76 (Min=0, Max=1; APOGEE2 score is 0.582), which predicts a damaging effect on gene function (PP3). Cybrid studies showed that this variant can either be deleterious or beneficial depending on haplogroup and environmental context. The variant reduces both complex I activity and NADH-linked respiration especially when on non-M9 haplogroups. In Asia, this variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, this variant is enriched on the M9 background in Tibet. When present on the M9 background, this variant is associated with a complex I activity that is equal to or higher than that of the wild type sequence on other haplotype backgrounds (B4c and F1; PMID: 22517755). In a cybrid study of East Asian metabolic syndrome (PMID: 29997041), complex I activity of the cells with this variant had lower complex I activity than cells with the wild type sequence, and that these lower complex I levels correlated with increased risk for metabolic phenotypes. Addition of this variant further reduced the complex I activity on cybrids of B4c, F1, and M9 haplogroup backgrounds (PS3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on September 11, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PP3, PS3_supporting, PS4. |
| ARUP Laboratories, |
RCV000507319 | SCV000604438 | pathogenic | not provided | 2017-05-12 | criteria provided, single submitter | clinical testing | The m.3394T>C variant is found at a frequency of 1.3% in MITOMAP (identified in 409 out of 32,059 sequences). When this variant has been reported in Leber hereditary optic neuropathy (LHON) patients, it is typically found alongside a primary variant; normally m.14484T>C (Brown 1995). The exact contribution of secondary variants such as m.3394T>C to the LHON phenotype is not fully understood, although data indicate that m.3394T>C likely influences the LHON phenotype in an ethnic-specific manner. While the frequency of m.3394T>C in Japanese LHON patients was not increased over controls (Matsumoto 1999), this mutation was found in 8.5% of Caucasian LHON patients compared to 1.1% of controls (Brown 1995). Furthermore, m.3394T>C was identified in four Chinese families effected with a low penetrance form of LHON (Liang 2009). m.3394T>C was identified in these families in the absence of any primary variant, suggesting that it plays a critical role in the LHON phenotype, either in isolation or by modifying other as-yet unidentified factors. |
| Wong Mito Lab, |
RCV000853650 | SCV000996678 | benign | Leigh syndrome | 2019-10-17 | criteria provided, single submitter | clinical testing | The NC_012920.1:m.3394T>C (YP_003024026.1:p.Tyr30His) variant in MTND1 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2 |
| OMIM | RCV000010375 | SCV000030601 | pathogenic | Leber optic atrophy | 1992-11-01 | no assertion criteria provided | literature only | |
| Institute of Human Genetics, |
RCV004814878 | SCV005069533 | uncertain significance | Optic atrophy | 2022-01-01 | no assertion criteria provided | clinical testing |