ClinVar Miner

Submissions for variant NM_002437.5(MPV17):c.293C>T (p.Pro98Leu) (rs267607258)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198122 SCV000251738 pathogenic not provided 2017-05-31 criteria provided, single submitter clinical testing p.Pro98Leu (CCG>CTG): c.293 C>T in exon 5 of the MPV17 gene (NM_002437.4). The P98L missense mutation in the MPV17 gene has been reported previously in association with mitochondrial DNA depletion syndrome including in a patient from Pakistan who was homozygous for P98L (El-Hattab et al., 2010; Blakely et al., 2012). The variant is found in MITONUC-MITOP panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000312148 SCV000429733 pathogenic MPV17-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000198122 SCV000855273 pathogenic not provided 2018-04-19 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000031911 SCV000998880 pathogenic Navajo neurohepatopathy 2019-08-13 criteria provided, single submitter curation 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.
Invitae RCV000198122 SCV001411082 pathogenic not provided 2019-08-21 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 98 of the MPV17 protein (p.Pro98Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs267607258, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another MPV17 variant in individuals with mitochondrial DNA depletion syndrome (PMID: 20074988, 27536553, 23714749, 25129007, 22508010). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 38355). This variant has been reported to affect MPV17 protein function (PMID: 25861990) For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company RCV001250252 SCV001424457 pathogenic Mitochondrial DNA depletion syndrome type 6 criteria provided, single submitter clinical testing
GeneReviews RCV000031911 SCV000054546 pathologic Navajo neurohepatopathy 2012-05-17 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000768420 SCV000899172 pathogenic Charcot-marie-tooth disease, axonal, type 2ee 2019-04-29 no assertion criteria provided literature only
Natera, Inc. RCV000031911 SCV001462524 pathogenic Navajo neurohepatopathy 2020-09-16 no assertion criteria provided clinical testing

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