NM_002437.5(MPV17):c.121C>T (p.Arg41Trp) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 22, 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:: RCV000734836.13

Allele description [Variation Report for NM_002437.5(MPV17):c.121C>T (p.Arg41Trp)]

NM_002437.5(MPV17):c.121C>T (p.Arg41Trp)

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.121C>T (p.Arg41Trp)

Other names:

p.R41W:CGG>TGG

HGVS:

NC_000002.12:g.27313059G>A
NG_008075.1:g.14506C>T
NG_033055.1:g.205C>T
NM_002437.5:c.121C>TMANE SELECT
NP_002428.1:p.Arg41Trp
NC_000002.11:g.27535926G>A
NM_002437.4:c.121C>T

Protein change:

R41W

Links:

dbSNP: rs863224072

NCBI 1000 Genomes Browser:

rs863224072

Molecular consequence:

NM_002437.5:c.121C>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
SCV002287895	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 22, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23714749, 28673863, 31319225, 33486010, 26437932, 30298599, 28492532
SCV003832762	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 28, 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

SCV002287895

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 22, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV003832762

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 28, 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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene.

Uusimaa J, Evans J, Smith C, Butterworth A, Craig K, Ashley N, Liao C, Carver J, Diot A, Macleod L, Hargreaves I, Al-Hussaini A, Faqeih E, Asery A, Al Balwi M, Eyaid W, Al-Sunaid A, Kelly D, van Mourik I, Ball S, Jarvis J, Mulay A, et al.

Eur J Hum Genet. 2014 Feb;22(2):184-91. doi: 10.1038/ejhg.2013.112. Epub 2013 May 29.

PubMed [citation]

PMID:: 23714749
PMCID:: PMC3895632

MPV17 hepatocerebral mitochondrial DNA depletion syndrome presenting as acute flaccid paralysis - A case report.

Pyal A, Paramasivam A, Meena AK, Bhavana VB, Thangaraj K.

Mitochondrion. 2017 Nov;37:41-45. doi: 10.1016/j.mito.2017.06.006. Epub 2017 Jun 30.

PubMed [citation]

PMID:: 28673863

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000251736.11

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

Description

p.Arg41Trp (CGG>TGG): c.121 C>T in exon 3 of the MPV17 gene (NM_002437.4). The R41W variant has not been reported as a benign polymorphism to our knowledge. R41W has been reported in association with mitochondrial DNA depletion syndrome in two affected siblings who were each homozygous for R41W (Uusimaa et al., 2014). The R41W 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 where amino acids with similar properties as Arginine are conserved across species. Missense mutations in nearby residues (Q36P, R50W, R50Q) have been reported in association with mitochondrial DNA depletion syndrome, supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).

#	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), SCV000863009.1

#	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, SCV002287895.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 41 of the MPV17 protein (p.Arg41Trp). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 23714749, 28673863, 31319225, 33486010). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214660). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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: 26437932, 30298599). 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 Revvity Omics, Revvity, SCV003832762.2

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000251736	GeneDx	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (GeneDx Variant Classification (06012015))	Uncertain significance (Nov 19, 2014)	germline	clinical testing	Citation Link,
SCV000863009	Eurofins Ntd Llc (ga)	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (EGL ClinVar v180209 classification definitions)	Uncertain significance (Aug 22, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000251736

GeneDx

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(GeneDx Variant Classification (06012015))

Uncertain significance
(Nov 19, 2014)

germline

clinical testing

Citation Link,

SCV000863009

Eurofins Ntd Llc (ga)

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(EGL ClinVar v180209 classification definitions)

Uncertain significance
(Aug 22, 2018)

germline

clinical testing

Citation Link

Last Updated: Sep 29, 2024

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