Submissions for variant NM_002437.5(MPV17):c.149G>A (p.Arg50Gln)

gnomAD frequency: 0.00003  dbSNP: rs121909721

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000712314	SCV000842780	pathogenic	not provided	2022-02-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Computational tools predict that this variant is damaging.
Eurofins Ntd Llc (ga)	RCV000712314	SCV000862602	pathogenic	not provided	2018-07-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000712314	SCV001202706	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 50 of the MPV17 protein (p.Arg50Gln). This variant is present in population databases (rs121909721, gnomAD 0.003%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome or Navajo neurohepatopathy (PMID: 16582910, 16909392, 28209105). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16160). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MPV17 function (PMID: 16582910, 30833296). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509162	SCV002819528	pathogenic	Mitochondrial DNA depletion syndrome	2022-12-14	criteria provided, single submitter	clinical testing	Variant summary: MPV17 c.149G>A (p.Arg50Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251478 control chromosomes (gnomAD). c.149G>A has been reported in the literature in multiple homozygous individuals affected with Mitochondrial DNA Depletion Syndrome (MPV17 Related disorder) and the variant segregated with the disease (examples: Spinazzola_2006 and Karadimas_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence suggesting that the R50Q mutation causes protein instability and decay (Karadimas_2006). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003466861	SCV004193739	pathogenic	Charcot-Marie-Tooth disease, axonal, type 2EE	2024-03-27	criteria provided, single submitter	clinical testing
OMIM	RCV000017543	SCV000037815	pathogenic	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	2006-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000017543	SCV000054537	not provided	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)		no assertion provided	literature only
Natera, Inc.	RCV000017543	SCV001462529	pathogenic	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732550	SCV005362666	pathogenic	MPV17-related disorder	2024-04-03	no assertion criteria provided	clinical testing	The MPV17 c.149G>A variant is predicted to result in the amino acid substitution p.Arg50Gln. This variant has been previously reported to be pathogenic for the autosomal recessive hepatocerebral form of mitochondrial DNA depletion syndrome (Spinazzola et al. 2006. PubMed ID: 16582910; Shimura et al. 2020. PubMed ID: 32703289). It has been also documented as a founder pathogenic variant for Navajo neurohepatopathy among Navajo children in the southwestern United States (Karadimas et al. 2006. PubMed ID: 16909392). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org). This variant is interpreted as pathogenic.