Submissions for variant NM_002437.5(MPV17):c.263A>T (p.Lys88Met)

gnomAD frequency: 0.00004  dbSNP: rs756530281

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002037482	SCV002115631	likely pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing	This variant, c.263_265delinsTGT, is a complex sequence change that results in the deletion of 2 and insertion of 2 amino acid(s) in the MPV17 protein (p.Lys88_Met89delinsMetLeu). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with clinical features of mitochondrial DNA depletion syndrome (PMID: 22964873). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV002037482	SCV003916080	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	MPV17: PM2, PM5:Supporting
Neuberg Centre For Genomic Medicine, NCGM	RCV004546675	SCV005042972	likely pathogenic	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)		criteria provided, single submitter	clinical testing	The missense c.263A>Tp.Lys88Met variant in MPV17 gene has been reported previously in compound heterozygous state in individuals affected with mitochondrial DNA depletion syndrome Garone et al., 2012. This variant is reported with the allele frequency of 0.006% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic. The amino acid Lys at position 88 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Lys88Met in MPV17 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. In at least one individual the data is consistent with being in trans on the opposite chromosome from a pathogenic variant. For these reasons, this variant has been classified as Likely Pathogenic.