Submissions for variant NM_002437.5(MPV17):c.373C>T (p.Arg125Trp)

gnomAD frequency: 0.00007  dbSNP: rs112170670

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000338177	SCV000429731	uncertain significance	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV003227479	SCV000429732	uncertain significance	Mitochondrial DNA depletion syndrome 15 (hepatocerebral type)	2016-06-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000730532	SCV000858277	uncertain significance	not provided	2018-06-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000730532	SCV001823451	uncertain significance	not provided	2019-04-11	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in the unaffected father of a fetus with short rib-polydactyly syndrome type III which was attributed to compound heterozygous variants identified in the DYNC2H1 gene (Chen et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; If c.373 C>T does not alter splicing, it will result in the R125W missense change. In silico analysis, which include protein predictors and evolutionary conservation, supports a deleterious effect.; This variant is associated with the following publications: (PMID: 27323140)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000730532	SCV003459228	uncertain significance	not provided	2022-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 125 of the MPV17 protein (p.Arg125Trp). This variant is present in population databases (rs112170670, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MPV17-related conditions. ClinVar contains an entry for this variant (Variation ID: 335526). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	RCV003320359	SCV003930388	uncertain significance	Charcot-Marie-Tooth disease, axonal, type 2EE	2024-05-22	criteria provided, single submitter	research	PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.00020 (0.02%; 5/24944 alleles in African/African American population) and the variant is absent from an internal database of 1074 control alleles. PP3_met: Revel score is 0.657. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
Breakthrough Genomics, Breakthrough Genomics	RCV000730532	SCV005188331	uncertain significance	not provided		criteria provided, single submitter	not provided
Natera, Inc.	RCV003227479	SCV002076538	uncertain significance	Mitochondrial DNA depletion syndrome 15 (hepatocerebral type)	2020-01-17	no assertion criteria provided	clinical testing