NM_002437.5(MPV17):c.148C>T (p.Arg50Trp) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jul 29, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000264441.23

Allele description [Variation Report for NM_002437.5(MPV17):c.148C>T (p.Arg50Trp)]

NM_002437.5(MPV17):c.148C>T (p.Arg50Trp)

Gene:

MPV17:mitochondrial inner membrane protein MPV17 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p23.3

Genomic location:

Preferred name:

NM_002437.5(MPV17):c.148C>T (p.Arg50Trp)

HGVS:

NC_000002.12:g.27313032G>A
NG_008075.1:g.14533C>T
NG_033055.1:g.232C>T
NM_002437.5:c.148C>TMANE SELECT
NP_002428.1:p.Arg50Trp
NC_000002.11:g.27535899G>A
NM_002437.4:c.148C>T
P39210:p.Arg50Trp

Protein change:

R50W; ARG50TRP

Links:

UniProtKB: P39210#VAR_026218; OMIM: 137960.0003; dbSNP: rs121909723

NCBI 1000 Genomes Browser:

rs121909723

Molecular consequence:

NM_002437.5:c.148C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329729	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Aug 28, 2016)	germline	clinical testing	Citation Link,
SCV000701930	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Oct 4, 2016)	germline	clinical testing	Citation Link,
SCV000951366	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 29, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16909392, 16582910, 17694548, 25016221, 28492532
SCV002017537	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 27, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Navajo neurohepatopathy is caused by a mutation in the MPV17 gene.

Karadimas CL, Vu TH, Holve SA, Chronopoulou P, Quinzii C, Johnsen SD, Kurth J, Eggers E, Palenzuela L, Tanji K, Bonilla E, De Vivo DC, DiMauro S, Hirano M.

Am J Hum Genet. 2006 Sep;79(3):544-8. Epub 2006 Jun 28.

PubMed [citation]

PMID:: 16909392
PMCID:: PMC1559552

MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion.

Spinazzola A, Viscomi C, Fernandez-Vizarra E, Carrara F, D'Adamo P, Calvo S, Marsano RM, Donnini C, Weiher H, Strisciuglio P, Parini R, Sarzi E, Chan A, DiMauro S, Rötig A, Gasparini P, Ferrero I, Mootha VK, Tiranti V, Zeviani M.

Nat Genet. 2006 May;38(5):570-5. Epub 2006 Apr 2.

PubMed [citation]

PMID:: 16582910

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000329729.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The R50W pathogenic variant in the MPV17 gene has been reported previously in multiple individuals with clinical features consistent with hepatocerebral mitochondrial DNA depletion syndrome in the homozygous state, as well as in the heterozygous state in the presence of a second MPV17 variant (Spinazzola et al., 2006; Wong et al., 2007; Vilarinho et al., 2014). Additionally, functional studies in yeast with the R50W variant show that this variant impacts the function of the protein (Spinazzola et al., 2006). The R50W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R50W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R50W as a pathogenic variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000701930.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000951366.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Experimental studies have shown that this missense change affects MPV17 function (PMID: 16582910). This variant disrupts the p.Arg50 amino acid residue in MPV17. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16582910, 16909392). 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. 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. ClinVar contains an entry for this variant (Variation ID: 16162). This missense change has been observed in individual(s) with clinical features of MPV17-related conditions (PMID: 16582910, 17694548, 25016221). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121909723, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 50 of the MPV17 protein (p.Arg50Trp).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002017537.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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