Submissions for variant NC_012920.1(MT-CYB):m.1630A>G

dbSNP: rs1603218588

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV003153871	SCV003842279	uncertain significance	Mitochondrial disease	2022-11-14	reviewed by expert panel	curation	The m.1630A>G variant in MT-TV has been reported in two unrelated individuals. One individual had features consistent with mitochondrial neurogastrointestinal encephalopathy (MNGIE) with additional features of hearing loss, mild psychomotor delay, headache, and small stature (PMID: 19252805). Another individual had features consistent with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in addition to bilateral sensorineural hearing loss, myopia, short stature requiring growth hormone supplementation, and delayed onset of puberty (PMID: 21540128; PS4_supporting). The variant was heteroplasmic in the individual with MNGIE-like features at 90% in muscle and 70% in blood, with 60% heteroplasmy being seen in the asymptomatic mother’s blood (PMID: 19252805). In the individual with MELAS, the variant was present at 75% heteroplasmy in blood, 95% in urine, and 90% in fibroblasts; the variant was present in the mother at 93% in blood, 98% in urine, and 95% in fibroblasts (PMIDs: 21540128, 30709774). No correlating segregations or de novo occurrences of this variant were found in our review of the literature. The computational predictor MitoTIP suggests this variant is pathogenic (65th percentile) and HmtVAR predicts it to be pathogenic score of 0.85 (PP3). The m.1630A>G variant is absent in the GenBank dataset, the Helix dataset (although there are four heteroplasmic occurrences), and gnomAD3.1.2 (PM2_supporting). Single-fiber testing (PMID: 19252805) showed 90% heteroplasmy in COX-negative fibers and 50% in COX-positive fibers. Cybrids showed marked decrease in cytochrome-c oxidase activity. Oxygen consumption/respiration activity was also greatly reduced in both homoplasmic and heteroplasmic cybrid lines. Northern blotting showed a pronounced loss of MTTV in mutant cybrids when compared to controls (PMID: 21540128; PS3_supporting). Electron transport enzyme activities were assessed in one of the individuals and her healthy mother, and showed a significant difference between the proband and the mother and a healthy control individual. Exome sequencing was performed in the proband and her mother, ruling out other known genetic etiologies (PMID: 30709774; PP4). 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 November 14, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PP3, PM2_supporting, PS3_supporting, PP4.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000850670	SCV000992901	likely pathogenic	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2019-07-12	criteria provided, single submitter	clinical testing	The NC_012920.1:m.1630A>G variant in MT-TV gene is interpreted to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PM7, PP4, PP6
Mendelics	RCV000850670	SCV002517735	uncertain significance	Juvenile myopathy, encephalopathy, lactic acidosis AND stroke	2023-06-19	criteria provided, single submitter	clinical testing