Submissions for variant m.4171C>A

dbSNP: rs28616230

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV002260596	SCV002540725	uncertain significance	Mitochondrial disease	2022-06-30	reviewed by expert panel	curation	The m.4171C>A (p.L289M) variant in MT-ND1 has been reported in 13 individuals with primary mitochondrial disease with features falling under the LHON and/or Leigh syndrome spectrums with variable brain lesions (PS4_moderate, PMIDs: 12112111, 19555656, 20491810, 22879922, 24884847, 32652755, 34670133, 35104579, 32045392; Cui et al., 2006 with no PMID; of note, the two families in PMID: 12112111 might be in the same haplogroup although there is no known kinship). Additionally, this expert panel knew of one local family with an affected individual with this variant that the expert panel agreed to include. There are no reports of de novo occurrences to our knowledge. Although typically homoplasmic in kindreds, the variant has been reported to segregate with features of primary mitochondrial disease in two family members from one family (PMID: 12112111) however this did not meet criteria to be considered for PP1. This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (two occurrences in GenBank sequences are from individuals with mitochondrial disease; absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.60 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). An E. coli model (homoplasmic for this variant) showed only a 13% decrease in enzyme activity, which did not reach statistical significance and therefore did not meet criteria to be considered for PS3 (PMID: 19616643). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. In the future, once three or more unrelated cases are reported, criteria for a likely pathogenic classification would be met. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on April 11, 2022 (PMID: 32906214): Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PM2_supporting, PP3.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000010384	SCV000996776	likely pathogenic	Leber optic atrophy	2019-10-17	criteria provided, single submitter	clinical testing	The NC_012920.1:m.4171C>A (YP_003024026.1:p.Leu289Met) 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, PM9, PP4
Mendelics	RCV000010384	SCV002517669	pathogenic	Leber optic atrophy	2022-05-04	criteria provided, single submitter	clinical testing
OMIM	RCV000010384	SCV000030610	pathogenic	Leber optic atrophy	2002-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000010384	SCV000086638	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.