The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Computational tools predict that this variant is damaging.
ClinVar Genomic variation as it relates to human health
NM_002437.5(MPV17):c.149G>A (p.Arg50Gln)
Germline
Classification
Help
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.
(9)
Help
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.
Pathogenic
9
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.149G>A (p.Arg50Gln)
Variation ID: 16160 Accession: VCV000016160.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p23.3 2: 27313031 (GRCh38) [ NCBI UCSC ] 2: 27535898 (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 Apr 4, 2013 Oct 8, 2024 Mar 27, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002437.5:c.149G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002428.1:p.Arg50Gln missense NC_000002.12:g.27313031C>T NC_000002.11:g.27535898C>T NG_008075.1:g.14534G>A NG_033055.1:g.233G>A P39210:p.Arg50Gln - Protein change
- R50Q
- Other names
- -
- Canonical SPDI
- NC_000002.12:27313030:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic (3) |
no assertion criteria provided
|
Sep 16, 2020 | RCV000017543.30 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 18, 2024 | RCV000712314.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 27, 2024 | RCV003466861.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 14, 2022 | RCV002509162.1 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 3, 2024 | RCV004732550.1 |
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
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Charcot-Marie-Tooth disease, axonal, type 2EE
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004193739.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jul 24, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000862602.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Feb 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV000842780.3
First in ClinVar: Oct 20, 2018 Last updated: Dec 31, 2022 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Computational tools predict … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Computational tools predict that this variant is damaging. (less)
|
|
|
Pathogenic
(Dec 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mitochondrial DNA depletion syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819528.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
Variant summary: MPV17 c.149G>A (p.Arg50Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: MPV17 c.149G>A (p.Arg50Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251478 control chromosomes (gnomAD). c.149G>A has been reported in the literature in multiple homozygous individuals affected with Mitochondrial DNA Depletion Syndrome (MPV17 Related disorder) and the variant segregated with the disease (examples: Spinazzola_2006 and Karadimas_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence suggesting that the R50Q mutation causes protein instability and decay (Karadimas_2006). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001202706.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 50 of the MPV17 protein (p.Arg50Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 50 of the MPV17 protein (p.Arg50Gln). This variant is present in population databases (rs121909721, gnomAD 0.003%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome or Navajo neurohepatopathy (PMID: 16582910, 16909392, 28209105). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16160). 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. Experimental studies have shown that this missense change affects MPV17 function (PMID: 16582910, 30833296). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 01, 2006)
|
no assertion criteria provided
Method: literature only
|
MITOCHONDRIAL DNA DEPLETION SYNDROME 6 (HEPATOCEREBRAL TYPE)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000037815.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In affected members of a southern Italian family with mitochondrial DNA depletion syndrome-6 (MTDPS6; 256810), manifest with hepatic and cerebral involvement, Spinazzola et al. (2006) … (more)
In affected members of a southern Italian family with mitochondrial DNA depletion syndrome-6 (MTDPS6; 256810), manifest with hepatic and cerebral involvement, Spinazzola et al. (2006) found homozygosity for a 149G-A transition in exon 2 of the MPV17 gene, resulting in an arg50-to-gln (R50Q) substitution. Karadimas et al. (2006) found the R50Q mutation as the basis of MTDPS6, also called Navajo neurohepatopathy because it was described as a founder disorder in the Navajo population of the southwestern United States. (less)
|
|
|
Pathogenic
(Apr 03, 2024)
|
no assertion criteria provided
Method: clinical testing
|
MPV17-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005362666.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The MPV17 c.149G>A variant is predicted to result in the amino acid substitution p.Arg50Gln. This variant has been previously reported to be pathogenic for the … (more)
The MPV17 c.149G>A variant is predicted to result in the amino acid substitution p.Arg50Gln. This variant has been previously reported to be pathogenic for the autosomal recessive hepatocerebral form of mitochondrial DNA depletion syndrome (Spinazzola et al. 2006. PubMed ID: 16582910; Shimura et al. 2020. PubMed ID: 32703289). It has been also documented as a founder pathogenic variant for Navajo neurohepatopathy among Navajo children in the southwestern United States (Karadimas et al. 2006. PubMed ID: 16909392). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org). This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Navajo neurohepatopathy
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001462529.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000054537.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
Variant summary: MPV17 c.149G>A (p.Arg50Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251478 control chromosomes (gnomAD). c.149G>A has been reported in the literature in multiple homozygous individuals affected with Mitochondrial DNA Depletion Syndrome (MPV17 Related disorder) and the variant segregated with the disease (examples: Spinazzola_2006 and Karadimas_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence suggesting that the R50Q mutation causes protein instability and decay (Karadimas_2006). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 50 of the MPV17 protein (p.Arg50Gln). This variant is present in population databases (rs121909721, gnomAD 0.003%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome or Navajo neurohepatopathy (PMID: 16582910, 16909392, 28209105). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16160). 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. Experimental studies have shown that this missense change affects MPV17 function (PMID: 16582910, 30833296). For these reasons, this variant has been classified as Pathogenic.
Comment:
The MPV17 c.149G>A variant is predicted to result in the amino acid substitution p.Arg50Gln. This variant has been previously reported to be pathogenic for the autosomal recessive hepatocerebral form of mitochondrial DNA depletion syndrome (Spinazzola et al. 2006. PubMed ID: 16582910; Shimura et al. 2020. PubMed ID: 32703289). It has been also documented as a founder pathogenic variant for Navajo neurohepatopathy among Navajo children in the southwestern United States (Karadimas et al. 2006. PubMed ID: 16909392). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org). This variant is interpreted as pathogenic.
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:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Computational tools predict that this variant is damaging.
Comment:
Variant summary: MPV17 c.149G>A (p.Arg50Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251478 control chromosomes (gnomAD). c.149G>A has been reported in the literature in multiple homozygous individuals affected with Mitochondrial DNA Depletion Syndrome (MPV17 Related disorder) and the variant segregated with the disease (examples: Spinazzola_2006 and Karadimas_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence suggesting that the R50Q mutation causes protein instability and decay (Karadimas_2006). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 50 of the MPV17 protein (p.Arg50Gln). This variant is present in population databases (rs121909721, gnomAD 0.003%). This missense change has been observed in individuals with mitochondrial DNA depletion syndrome or Navajo neurohepatopathy (PMID: 16582910, 16909392, 28209105). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16160). 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. Experimental studies have shown that this missense change affects MPV17 function (PMID: 16582910, 30833296). For these reasons, this variant has been classified as Pathogenic.
Comment:
The MPV17 c.149G>A variant is predicted to result in the amino acid substitution p.Arg50Gln. This variant has been previously reported to be pathogenic for the autosomal recessive hepatocerebral form of mitochondrial DNA depletion syndrome (Spinazzola et al. 2006. PubMed ID: 16582910; Shimura et al. 2020. PubMed ID: 32703289). It has been also documented as a founder pathogenic variant for Navajo neurohepatopathy among Navajo children in the southwestern United States (Karadimas et al. 2006. PubMed ID: 16909392). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and molecular basis of hepatocerebral mitochondrial DNA depletion syndrome in Japan: evaluation of outcomes after liver transplantation. | Shimura M | Orphanet journal of rare diseases | 2020 | PMID: 32703289 |
| The zebrafish orthologue of the human hepatocerebral disease gene MPV17 plays pleiotropic roles in mitochondria. | Martorano L | Disease models & mechanisms | 2019 | PMID: 30833296 |
| Pathological alleles of MPV17 modeled in the yeast Saccharomyces cerevisiae orthologous gene SYM1 reveal their inability to take part in a high molecular weight complex. | Gilberti M | PloS one | 2018 | PMID: 30273399 |
| MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects. | El-Hattab AW | Human mutation | 2018 | PMID: 29282788 |
| MPV17-Related Mitochondrial DNA Maintenance Defect. | Adam MP | - | 2018 | PMID: 22593919 |
| Navajo Neurohepatopathy : A Case Report and Literature Review Emphasizing Clinicopathologic Diagnosis. | Bitting CP | Acta gastro-enterologica Belgica | 2016 | PMID: 28209105 |
| MPV17-associated hepatocerebral mitochondrial DNA depletion syndrome: new patients and novel mutations. | El-Hattab AW | Molecular genetics and metabolism | 2010 | PMID: 20074988 |
| Glucose metabolism and diet-based prevention of liver dysfunction in MPV17 mutant patients. | Parini R | Journal of hepatology | 2009 | PMID: 19012992 |
| Lack of founder effect for an identical mtDNA depletion syndrome (MDS)-associated MPV17 mutation shared by Navajos and Italians. | Spinazzola A | Neuromuscular disorders : NMD | 2008 | PMID: 18261905 |
| Navajo neurohepatopathy is caused by a mutation in the MPV17 gene. | Karadimas CL | American journal of human genetics | 2006 | PMID: 16909392 |
| MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. | Spinazzola A | Nature genetics | 2006 | PMID: 16582910 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MPV17 | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs121909721 ...
HelpThese 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 Oct 13, 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.