NM_002437.5(MPV17):c.122G>A (p.Arg41Gln) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 14, 2024
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:: RCV000792530.19

Allele description [Variation Report for NM_002437.5(MPV17):c.122G>A (p.Arg41Gln)]

NM_002437.5(MPV17):c.122G>A (p.Arg41Gln)

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.122G>A (p.Arg41Gln)

HGVS:

NC_000002.12:g.27313058C>T
NG_008075.1:g.14507G>A
NG_033055.1:g.206G>A
NM_002437.5:c.122G>AMANE SELECT
NP_002428.1:p.Arg41Gln
NC_000002.11:g.27535925C>T
NM_002437.4:c.122G>A

Protein change:

R41Q; ARG41GLN

Links:

OMIM: 137960.0009; dbSNP: rs140992482

NCBI 1000 Genomes Browser:

rs140992482

Molecular consequence:

NM_002437.5:c.122G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000931833	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 14, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 30298599, 26437932, 23714749, 28673863, 28492532
SCV001810684	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 27, 2021)	germline	clinical testing	Citation Link,
SCV003819641	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000931833

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 14, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001810684

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 27, 2021)

germline

clinical testing

Citation Link,

SCV003819641

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 17, 2022)

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	not provided	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

MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy.

Baumann M, Schreiber H, Schlotter-Weigel B, Löscher WN, Stucka R, Karall D, Strom TM, Bauer P, Krabichler B, Fauth C, Glaeser D, Senderek J.

Clin Genet. 2019 Jan;95(1):182-186. doi: 10.1111/cge.13462. Epub 2018 Oct 25.

PubMed [citation]

PMID:: 30298599

A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy.

Choi YR, Hong YB, Jung SC, Lee JH, Kim YJ, Park HJ, Lee J, Koo H, Lee JS, Jwa DH, Jung N, Woo SY, Kim SB, Chung KW, Choi BO.

BMC Neurol. 2015 Oct 5;15:179. doi: 10.1186/s12883-015-0430-1.

PubMed [citation]

PMID:: 26437932
PMCID:: PMC4595119

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000931833.6

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 41 of the MPV17 protein (p.Arg41Gln). This variant is present in population databases (rs140992482, gnomAD 0.004%). This missense change has been observed in individuals with axonal sensorimotor neuropathy (PMID: 26437932, 30298599). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 626263). 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 not expected to disrupt MPV17 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects MPV17 function (PMID: 26437932). This variant disrupts the p.Arg41 amino acid residue in MPV17. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23714749, 28673863). 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.

#	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 GeneDx, SCV001810684.1

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

Description

Published functional studies demonstrate a damaging effect as R41Q significantly inhibited cellular proliferation as compared to wild type and induced mtDNA depletion (Choi et al., 2015); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31130284, 26437932, 30298599, 27535533)

#	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 Revvity Omics, Revvity, SCV003819641.2

#	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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