Submissions for variant NM_002437.5(MPV17):c.121C>T (p.Arg41Trp)

gnomAD frequency: 0.00003  dbSNP: rs863224072

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000734836	SCV000251736	uncertain significance	not provided	2014-11-19	criteria provided, single submitter	clinical testing	p.Arg41Trp (CGG>TGG): c.121 C>T in exon 3 of the MPV17 gene (NM_002437.4). The R41W variant has not been reported as a benign polymorphism to our knowledge. R41W has been reported in association with mitochondrial DNA depletion syndrome in two affected siblings who were each homozygous for R41W (Uusimaa et al., 2014). The R41W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties as Arginine are conserved across species. Missense mutations in nearby residues (Q36P, R50W, R50Q) have been reported in association with mitochondrial DNA depletion syndrome, supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Eurofins Ntd Llc (ga)	RCV000734836	SCV000863009	uncertain significance	not provided	2018-08-22	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000855709	SCV000998884	likely pathogenic	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	2019-08-13	criteria provided, single submitter	curation	This variant is interpreted as a Likely pathogenic for Mitochondrial DNA depletion syndrome 6, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP1, PM5, PM3-supporting.
Invitae	RCV000734836	SCV002287895	pathogenic	not provided	2023-12-22	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 41 of the MPV17 protein (p.Arg41Trp). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 23714749, 28673863, 31319225, 33486010). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214660). 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. This variant disrupts the p.Arg41 amino acid residue in MPV17. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26437932, 30298599). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000734836	SCV003832762	likely pathogenic	not provided	2022-09-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468889	SCV004193733	likely pathogenic	Charcot-Marie-Tooth disease, axonal, type 2EE	2023-10-23	criteria provided, single submitter	clinical testing