ClinVar Miner

Submissions for variant m.3635G>A

dbSNP: rs397515507
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen RCV002291214 SCV002583528 likely pathogenic Mitochondrial disease 2022-08-23 reviewed by expert panel curation The m.3635G>A (p.S110N) variant in MT-ND1 has been reported in >16 individuals with primary mitochondrial disease, and more specifically Leber's hereditary optic neuropathy (LHON). This variant has been observed in affected individuals primarily in the homoplasmic state to date (20/21 cases) (PS4; PMIDs: 25194554, 21074518, 23304069,19527690, 19497304, 11479733, 33417421). There are no large families reported in the medical literature to consider for evidence of segregation. There are no reported de novo occurrences of this variant to our knowledge. This variant is absent in Helix and the GenBank dataset. It is present in gnomAD 3.1 in 1/56428 individuals (0.002%). Although there is one occurrence, the frequency is still low (PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.75 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMIDs: 25194554, 11479733). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on August 23, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM2_supporting, PS3_supporting, PP3, PS4.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000055707 SCV000996715 likely pathogenic Leber optic atrophy 2019-10-17 criteria provided, single submitter clinical testing The NC_012920.1:m.3635G>A (YP_003024026.1:p.Ser110Asn) variant in MTND1 gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM10, PP4
Mendelics RCV000055707 SCV002517663 pathogenic Leber optic atrophy 2022-05-04 criteria provided, single submitter clinical testing
GeneReviews RCV000055707 SCV000086633 not provided Leber optic atrophy no assertion provided literature only This mitochondrial DNA variant affects function. It hase been identified in at least two independent LHON pedigrees and segregates with affected disease status.

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