VCV000335526.27 - ClinVar

NM_002437.5(MPV17):c.373C>T (p.Arg125Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002437.5(MPV17):c.373C>T (p.Arg125Trp)

Variation ID: 335526 Accession: VCV000335526.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p23.3 2: 27312496 (GRCh38) [ NCBI UCSC ] 2: 27535363 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Aug 18, 2024	May 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002437.5:c.373C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002428.1:p.Arg125Trp	missense
NC_000002.12:g.27312496G>A
NC_000002.11:g.27535363G>A
NG_008075.1:g.15069C>T
NG_033055.1:g.768C>T

... more HGVS ... less HGVS

Protein change

R125W

Other names

Canonical SPDI

NC_000002.12:27312495:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00040 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Trans-Omics for Precision Medicine (TOPMed) 0.00011

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

Links

ClinGen: CA1575585 dbSNP: rs112170670 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MPV17		-	-	GRCh38 GRCh37	320	350

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)	Uncertain significance (1)	criteria provided, single submitter	Jan 12, 2018	RCV000338177.12
not provided	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Jul 11, 2022	RCV000730532.16
Mitochondrial DNA depletion syndrome 15 (hepatocerebral type)	Uncertain significance (2)	criteria provided, single submitter	Jun 14, 2016	RCV003227479.8
Charcot-Marie-Tooth disease, axonal, type 2EE	Uncertain significance (1)	criteria provided, single submitter	May 22, 2024	RCV003320359.10

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Hepatocerebral Mitochondrial DNA Depletion Syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000429732.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Jun 15, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000858277.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MPV17 Number of individuals with the variant: 2 Sex: mixed
Uncertain significance (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000429731.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Apr 11, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001823451.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: Identified in the heterozygous state in the unaffected father of a fetus with short rib-polydactyly syndrome type III which was attributed to compound heterozygous variants … (more) Identified in the heterozygous state in the unaffected father of a fetus with short rib-polydactyly syndrome type III which was attributed to compound heterozygous variants identified in the DYNC2H1 gene (Chen et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; If c.373 C>T does not alter splicing, it will result in the R125W missense change. In silico analysis, which include protein predictors and evolutionary conservation, supports a deleterious effect.; This variant is associated with the following publications: (PMID: 27323140) (less)
Uncertain significance (Jul 11, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003459228.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 125 of the MPV17 protein … (more) This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 125 of the MPV17 protein (p.Arg125Trp). This variant is present in population databases (rs112170670, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MPV17-related conditions. ClinVar contains an entry for this variant (Variation ID: 335526). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (May 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Charcot-Marie-Tooth disease, axonal, type 2EE (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neurogenomics Lab, Neuroscience Institute, University Of Cape Town Accession: SCV003930388.2 First in ClinVar: Aug 19, 2023 Last updated: May 26, 2024	Publications: PubMed (1) PubMed: 37712079 Comment: PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.00020 (0.02%; 5/24944 alleles in African/African American population) and the variant is absent from an … (more) PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.00020 (0.02%; 5/24944 alleles in African/African American population) and the variant is absent from an internal database of 1074 control alleles. PP3_met: Revel score is 0.657. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. (less) Number of individuals with the variant: 4 Sex: mixed Geographic origin: South Africa Comment on evidence: All 4 probands carry a second heterozygous MPV17 VUS NP_002428.1:p.Gln36Ter (not confirmed in trans).
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005188331.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024
Uncertain significance (Jan 17, 2020)	no assertion criteria provided Method: clinical testing	Mitochondrial DNA depletion syndrome, hepatocerebral form Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002076538.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

Identified in the heterozygous state in the unaffected father of a fetus with short rib-polydactyly syndrome type III which was attributed to compound heterozygous variants identified in the DYNC2H1 gene (Chen et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; If c.373 C>T does not alter splicing, it will result in the R125W missense change. In silico analysis, which include protein predictors and evolutionary conservation, supports a deleterious effect.; This variant is associated with the following publications: (PMID: 27323140)

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 125 of the MPV17 protein (p.Arg125Trp). This variant is present in population databases (rs112170670, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MPV17-related conditions. ClinVar contains an entry for this variant (Variation ID: 335526). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

PM2_supporting: the highest population allele frequency in gnomAD v4.0 is 0.00020 (0.02%; 5/24944 alleles in African/African American population) and the variant is absent from an internal database of 1074 control alleles. PP3_met: Revel score is 0.657. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia.	Mahungu AC	Frontiers in neurology	2023	PMID: 37712079
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MPV17	-	-	-	-

Text-mined citations for rs112170670 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_002437.5(MPV17):c.373C>T (p.Arg125Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs112170670 ...