NM_002437.5(MPV17):c.293C>T (p.Pro98Leu) AND MPV17-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 27, 2017
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000312148.14

Allele description [Variation Report for NM_002437.5(MPV17):c.293C>T (p.Pro98Leu)]

NM_002437.5(MPV17):c.293C>T (p.Pro98Leu)

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.293C>T (p.Pro98Leu)

Other names:

p.P98L:CCG>CTG

HGVS:

NC_000002.12:g.27312576G>A
NG_008075.1:g.14989C>T
NG_033055.1:g.688C>T
NM_002437.5:c.293C>TMANE SELECT
NP_002428.1:p.Pro98Leu
NC_000002.11:g.27535443G>A
NM_002437.4:c.293C>T
P39210:p.Pro98Leu

Note:

NCBI staff reviewed the trace in Figure 3 of the paper by Blakely et al., 2012 (PubMed 22508010) to clarify the definition of this variant.

Protein change:

P98L; PRO98LEU

Links:

UniProtKB: P39210#VAR_076203; OMIM: 137960.0008; dbSNP: rs267607258

NCBI 1000 Genomes Browser:

rs267607258

Molecular consequence:

NM_002437.5:c.293C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: MPV17-related disorder
Synonyms:: MPV17-Related Disorders; MPV17-related condition
Identifiers:: MedGen: CN239328

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000429733	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 25129007, 25861990, 20074988, 27536553, 26741492, 24190800, 23714749, 22508010 Citation Link,
SCV005363677	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Pathogenic (Mar 28, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000429733

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Pathogenic
(Apr 27, 2017)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV005363677

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Pathogenic
(Mar 28, 2024)

germline

clinical testing

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

Citations

PubMed

Mitochondrial DNA depletion syndrome causing liver failure.

Bijarnia-Mahay S, Mohan N, Goyal D, Verma IC.

Indian Pediatr. 2014 Aug;51(8):666-8.

PubMed [citation]

PMID:: 25129007

The Human Mitochondrial DNA Depletion Syndrome Gene MPV17 Encodes a Non-selective Channel That Modulates Membrane Potential.

Antonenkov VD, Isomursu A, Mennerich D, Vapola MH, Weiher H, Kietzmann T, Hiltunen JK.

J Biol Chem. 2015 May 29;290(22):13840-61. doi: 10.1074/jbc.M114.608083. Epub 2015 Apr 10.

PubMed [citation]

PMID:: 25861990
PMCID:: PMC4447960

See all PubMed Citations (8)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000429733.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The MPV17 c.293C>T (p.Pro98Leu) variant has been reported in at least eight studies in which it is found in a total of ten individuals with mitochondrial DNA depletion-related syndromes, including four in a homozygous state (two of whom were siblings) and six in a compound heterozygous state (El-Hattab et al. 2010; Blakely et al. 2012; Uusimaa et al. 2014; Mendelsohn et al. 2014; Bijarnia-Mahay et al. 2014; Harvengt et al. 2014; Kim et al. 2016; Khoda et al. 2016). Mitochondrial DNA was shown to be decreased by 20% in hepatic tissue in one of the compound heterozygous individuals (Khoda et al. 2016). The variant has also been detected in a heterozygous state in four unaffected relatives of probands. Control data are unavailable for this variant which is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. The MPV17 protein functions as a non-selective channel modulating the membrane potential to preserve mitochondrial homeostasis, and functional studies demonstrated that the p.Pro98Leu variant impacts the ability of the channel to close tightly (Antonenkov et al. 2015). Based on the evidence, the p.Pro98Leu variant is classified as pathogenic for MPV17-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 PreventionGenetics, part of Exact Sciences, SCV005363677.1

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

Description

The MPV17 c.293C>T variant is predicted to result in the amino acid substitution p.Pro98Leu. This variant has been reported in the homozygous and compound heterozygous states in individuals with mitochondrial DNA depletion syndrome (Blakely et al. 2012. PubMed ID: 22508010; Bijarnia-Mahay et al. 2014. PubMed ID: 25129007; Uusimaa et al. 2014. PubMed ID: 23714749; Kim et al. 2016. PubMed ID: 27536553; El-Hattab et al. 2010. PubMed ID: 20074988). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted 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

Last Updated: Nov 24, 2024

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