ClinVar Genomic variation as it relates to human health
NM_002437.5(MPV17):c.191C>G (p.Pro64Arg)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002437.5(MPV17):c.191C>G (p.Pro64Arg)
Variation ID: 381523 Accession: VCV000381523.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p23.3 2: 27312768 (GRCh38) [ NCBI UCSC ] 2: 27535635 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 8, 2017 Apr 15, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002437.5:c.191C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002428.1:p.Pro64Arg missense NC_000002.12:g.27312768G>C NC_000002.11:g.27535635G>C NG_008075.1:g.14797C>G NG_033055.1:g.496C>G - Protein change
- P64R
- Other names
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- Canonical SPDI
- NC_000002.12:27312767:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD) 0.00008
Exome Aggregation Consortium (ExAC) 0.00010
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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MPV17 | - | - |
GRCh38 GRCh37 |
311 | 340 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2024 | RCV000439109.26 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000855706.11 | |
not provided (1) |
no classification provided
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- | RCV003227483.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 10, 2023 | RCV003401418.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2023 | RCV003470380.1 |
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
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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
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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. |
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Pathogenic
(Dec 22, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000704815.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Likely pathogenic
(Aug 13, 2019)
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criteria provided, single submitter
Method: curation
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Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)
Affected status: unknown
Allele origin:
unknown
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SIB Swiss Institute of Bioinformatics
Accession: SCV000998879.1
First in ClinVar: Nov 15, 2019 Last updated: Nov 15, 2019 |
Comment:
This variant is interpreted as a Likely pathogenic for Mitochondrial DNA depletion syndrome 6, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PP1, … (more)
This variant is interpreted as a Likely pathogenic for Mitochondrial DNA depletion syndrome 6, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PP3, PP1, PM3. (less)
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Pathogenic
(Apr 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581906.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
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Likely pathogenic
(Nov 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000520842.6
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect … (more)
Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26437932, 29282788, 23829229, 23714749, 32827528, 33726816) (less)
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Pathogenic
(Oct 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004122688.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
Variant summary: MPV17 c.191C>G (p.Pro64Arg) results in a non-conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Five of … (more)
Variant summary: MPV17 c.191C>G (p.Pro64Arg) results in a non-conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251212 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MPV17 causing Mitochondrial DNA Depletion Syndrome - MPV17 Related (7.2e-05 vs 0.0011), allowing no conclusion about variant significance. c.191C>G has been reported in the literature in multiple individuals affected with Mitochondrial DNA Depletion Syndrome - MPV17 Related (Uusimaa_2014, Piekutowska-Abramczuk_2014), and at least one was reported as compound heterozygous with a pathogenic variant. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23714749, 23829229). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease, axonal, type 2EE
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004193729.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Apr 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003832751.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000945939.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 64 of the MPV17 protein (p.Pro64Arg). … (more)
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 64 of the MPV17 protein (p.Pro64Arg). This variant is present in population databases (rs375401970, gnomAD 0.02%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 23714749, 23829229). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381523). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV004697815.1
First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
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Likely pathogenic
(Jan 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004701282.2
First in ClinVar: Mar 10, 2024 Last updated: Apr 15, 2024 |
Comment:
MPV17: PM3:Strong, PM2, PM5
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Navajo neurohepatopathy
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001462527.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Mitochondrial DNA depletion syndrome, hepatocerebral form
Affected status: yes
Allele origin:
maternal
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GenomeConnect, ClinGen
Accession: SCV001423355.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
Comment:
Variant interpretted as Likely pathogenic and reported on 08-05-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the … (more)
Variant interpretted as Likely pathogenic and reported on 08-05-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of vision (present) , Myopia (disease) (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Anxiety (present) , Depressivity (present) , Abnormality … (more)
Abnormality of vision (present) , Myopia (disease) (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Anxiety (present) , Depressivity (present) , Abnormality of muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the stomach (present) , Abnormality of the bladder (present) , Periodontitis (present) , Gingivitis (present) (less)
Indication for testing: Diagnostic
Age: 20-29 years
Sex: female
Testing laboratory: GeneDx
Date variant was reported to submitter: 2019-08-05
Testing laboratory interpretation: Likely pathogenic
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene. | Uusimaa J | European journal of human genetics : EJHG | 2014 | PMID: 23714749 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MPV17 | - | - | - | - |
Text-mined citations for rs375401970 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.