ClinVar Genomic variation as it relates to human health

This variant is interpreted as a Likely pathogenic for Charcot-Marie-Tooth disease, axonal, 2EE, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP1, PS3-supporting, PM3.

Published functional studies demonstrate a damaging effect as R41Q significantly inhibited cellular proliferation as compared to wild type and induced mtDNA depletion (Choi et al., 2015); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31130284, 26437932, 30298599, 27535533)

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 41 of the MPV17 protein (p.Arg41Gln). This variant is present in population databases (rs140992482, gnomAD 0.004%). This missense change has been observed in individuals with axonal sensorimotor neuropathy (PMID: 26437932, 30298599). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 626263). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MPV17 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects MPV17 function (PMID: 26437932). 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: 23714749, 28673863). 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.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 26437932). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000626263). A different missense change at the same codon (p.Arg41Trp) has been reported to be associated with MPV17 related disorder (ClinVar ID: VCV000214660 / PMID: 23714749). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: MPV17 c.122G>A (p.Arg41Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251486 control chromosomes. c.122G>A has been reported in the literature as a homozygous genotype in multiple individuals affected with features of MPV17 related axonal sensorimotor polyneuropathy without liver and brain involvement, which is neurophysiologically similar to axonal Charcot-Marie-Tooth disease (CMT) (example, PMID: 30298599, 26437932). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting significantly inhibited cell proliferation when compared to controls (example, PMID: 26437932). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

PS3, PM2, PM5, PP2, PP5- The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 626263). Low frequency in gnomAD population databases. Functional studies support pathogenic effect (PMID: 26437932)

The MPV17 c.122G>A variant is predicted to result in the amino acid substitution p.Arg41Gln. This variant has been reported in the homozygous and compound heterozygous states in individuals with axonal sensorimotor polyneuropathy or Charcot-Marie-Tooth disease (see, for example, Choi et al. 2015. PubMed ID: 26437932; Baumann et al. 2019. PubMed ID: 30298599; Table S3, French et al. 2022. PubMed ID: 35586607). In vitro experimental studies suggest this variant impacts protein function (Choi et al. 2015. PubMed ID: 26437932; Ababneh et al. 2021. PubMed ID: 34624274). This variant is reported in 0.0046% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been consistently classified as pathogenic in ClinVar. This variant is interpreted as pathogenic.

Variant interpretted as Likely pathogenic and reported on 08-05-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.