ClinVar Genomic variation as it relates to human health

Variant summary: MPV17 c.293C>T (p.Pro98Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251314 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MPV17 causing Mitochondrial DNA Depletion Syndrome - MPV17 Related (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.293C>T has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome - MPV17 Related (e.g. Blakely_2015, El-Hattab_2010, Uusimaa_2014, Mundlamuri_2021). 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,that this variant may affect gating properties of the channel (Antonenkov_2015). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publications have been ascertained in the context of this evaluation (PMID: 25861990, 22508010, 20074988, 34979697, 23714749). All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The MPV17 c.293C>T (p.Pro98Leu) variant has been reported in at least eight studies in which it is found in a total of ten individuals with mitochondrial DNA depletion-related syndromes, including four in a homozygous state (two of whom were siblings) and six in a compound heterozygous state (El-Hattab et al. 2010; Blakely et al. 2012; Uusimaa et al. 2014; Mendelsohn et al. 2014; Bijarnia-Mahay et al. 2014; Harvengt et al. 2014; Kim et al. 2016; Khoda et al. 2016). Mitochondrial DNA was shown to be decreased by 20% in hepatic tissue in one of the compound heterozygous individuals (Khoda et al. 2016). The variant has also been detected in a heterozygous state in four unaffected relatives of probands. Control data are unavailable for this variant which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. The MPV17 protein functions as a non-selective channel modulating the membrane potential to preserve mitochondrial homeostasis, and functional studies demonstrated that the p.Pro98Leu variant impacts the ability of the channel to close tightly (Antonenkov et al. 2015). Based on the evidence, the p.Pro98Leu variant is classified as pathogenic for MPV17-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This variant is interpreted as a Pathogenic for Mitochondrial DNA depletion syndrome 6, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PS3-Moderate, PM3-Very Strong.

PM1, PM2, PP3, PP5

Published functional studies demonstrate a damaging effect as P98L results in a MPV17-channel that was prone to closing under reducing conditions and did not close completely compared to the wild-type channel (Antonenkov et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24190800, 22508010, 20074988, 23714749, 27536553, 27896091, 28776642, 32703289, 33083013, 34023347, 35314707, 34979697, 34052969, 25861990, 24077912)

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 98 of the MPV17 protein (p.Pro98Leu). This variant is present in population databases (rs267607258, gnomAD 0.02%). This missense change has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 20074988, 22508010, 23714749, 25129007, 27536553). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 38355). 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 expected to disrupt MPV17 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MPV17 function (PMID: 25861990). For these reasons, this variant has been classified as Pathogenic.

The MPV17 c.293C>T variant is predicted to result in the amino acid substitution p.Pro98Leu. This variant has been reported in the homozygous and compound heterozygous states in individuals with mitochondrial DNA depletion syndrome (Blakely et al. 2012. PubMed ID: 22508010; Bijarnia-Mahay et al. 2014. PubMed ID: 25129007; Uusimaa et al. 2014. PubMed ID: 23714749; Kim et al. 2016. PubMed ID: 27536553; El-Hattab et al. 2010. PubMed ID: 20074988). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.