Submissions for variant NM_002437.5(MPV17):c.191C>G (p.Pro64Arg)

gnomAD frequency: 0.00008  dbSNP: rs375401970

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000439109	SCV000520842	likely pathogenic	not provided	2024-12-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26437932, 23714749, 23829229, 37184518, 29282788, 32827528, 33726816, 37204315, 35586607)
Eurofins Ntd Llc (ga)	RCV000439109	SCV000704815	pathogenic	not provided	2016-12-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000439109	SCV000945939	pathogenic	not provided	2024-02-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 64 of the MPV17 protein (p.Pro64Arg). This variant is present in population databases (rs375401970, gnomAD 0.02%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 23714749, 23829229). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381523). 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%. For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics	RCV000855706	SCV000998879	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, PP3, PP1, PM3.
MGZ Medical Genetics Center	RCV000855706	SCV002581906	pathogenic	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	2022-04-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000439109	SCV003832751	likely pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401418	SCV004122688	pathogenic	Mitochondrial DNA depletion syndrome	2023-10-10	criteria provided, single submitter	clinical testing	Variant summary: MPV17 c.191C>G (p.Pro64Arg) results in a non-conservative amino acid change to a highly conserved residue (HGMD) 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 7.2e-05 in 251212 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MPV17 causing Mitochondrial DNA Depletion Syndrome - MPV17 Related (7.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.191C>G has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome - MPV17 Related (Uusimaa_2014, Piekutowska-Abramczuk_2014), and at least one was reported as compound heterozygous with a pathogenic variant. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23714749, 23829229). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003470380	SCV004193729	pathogenic	Charcot-Marie-Tooth disease, axonal, type 2EE	2024-02-26	criteria provided, single submitter	clinical testing
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000855706	SCV004697815	pathogenic	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	2024-03-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000439109	SCV004701282	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MPV17: PM3:Strong, PP1:Strong, PM2, PM5
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000439109	SCV005199165	likely pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005027487	SCV005655955	pathogenic	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type); Charcot-Marie-Tooth disease, axonal, type 2EE	2024-01-09	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV003227483	SCV001423355	not provided	Mitochondrial DNA depletion syndrome 15 (hepatocerebral type)		no assertion provided	phenotyping only	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.
Natera, Inc.	RCV000855706	SCV001462527	likely pathogenic	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	2020-09-16	no assertion criteria provided	clinical testing