ClinVar Genomic variation as it relates to human health
NM_000255.4(MMUT):c.607G>A (p.Gly203Arg)
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_000255.4(MMUT):c.607G>A (p.Gly203Arg)
Variation ID: 218987 Accession: VCV000218987.31
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p12.3 6: 49457837 (GRCh38) [ NCBI UCSC ] 6: 49425550 (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 Jan 16, 2016 May 12, 2024 Aug 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000255.4:c.607G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000246.2:p.Gly203Arg missense NC_000006.12:g.49457837C>T NC_000006.11:g.49425550C>T NG_007100.1:g.10303G>A P22033:p.Gly203Arg NP_000246.1:p.Gly203Arg - Protein change
- G203R
- Other names
- -
- Canonical SPDI
- NC_000006.12:49457836:C:T
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 | ||
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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
Help
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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MMUT | - | - |
GRCh38 GRCh37 |
1065 | 1078 |
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
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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 (2) |
criteria provided, single submitter
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Nov 16, 2017 | RCV000203339.6 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 16, 2023 | RCV001091103.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2023 | RCV003317150.2 | |
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency
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Pathogenic (1) |
no assertion criteria provided
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Mar 5, 2020 | RCV001833168.2 |
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. |
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Pathogenic
(Nov 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000795735.1
First in ClinVar: Jan 16, 2016 Last updated: Jan 16, 2016 |
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Pathogenic
(Dec 19, 2022)
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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: SCV002765556.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10923046, 17113806, 31525265, 32778825, 17432548, 33985557, 19375370, 35223700, 30041674, 32754920) (less)
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Pathogenic
(Jun 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Methylmalonic acidemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020521.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
Variant summary: MUT c.607G>A (p.Gly203Arg) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha chain, catalytic (IPR006098) of the encoded protein … (more)
Variant summary: MUT c.607G>A (p.Gly203Arg) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha chain, catalytic (IPR006098) of 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 1.6e-05 in 251262 control chromosomes. c.607G>A has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Examples: Forny_2016, Worgan_2006) These data indicate that the variant is very likely to be associated with disease. Two homozygous individuals show severely decreased enzyme activity (Forny_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27167370, 16281286). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 16, 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: SCV001385264.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 203 of the MUT protein (p.Gly203Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 203 of the MUT protein (p.Gly203Arg). This variant is present in population databases (rs778702777, gnomAD 0.003%). This missense change has been observed in individual(s) with methylmalonic aciduria (PMID: 10923046, 16281286, 17432548, 19375370). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 218987). 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 MUT protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 01, 2018)
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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: SCV001246958.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Mar 05, 2020)
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no assertion criteria provided
Method: clinical testing
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Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002075435.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000258498.2
First in ClinVar: Jan 16, 2016 Last updated: Oct 01, 2022
Comment:
mut0 enzymatic subtype
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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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Isolated Methylmalonic Acidemia. | Adam MP | - | 2022 | PMID: 20301409 |
Molecular Genetic Characterization of 151 Mut-Type Methylmalonic Aciduria Patients and Identification of 41 Novel Mutations in MUT. | Forny P | Human mutation | 2016 | PMID: 27167370 |
Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. | Nizon M | Orphanet journal of rare diseases | 2013 | PMID: 24059531 |
Neurocognitive phenotype of isolated methylmalonic acidemia. | O'Shea CJ | Pediatrics | 2012 | PMID: 22614770 |
Long-term outcome in methylmalonic aciduria: a series of 30 French patients. | Cosson MA | Molecular genetics and metabolism | 2009 | PMID: 19375370 |
Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group. | Merinero B | Journal of inherited metabolic disease | 2008 | PMID: 17957493 |
[Diagnosis and treatment of methylmalonic aciduria: a case report]. | Mahfoud A | Investigacion clinica | 2007 | PMID: 17432548 |
Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut- methylmalonic aciduria: identification of seven novel mutations. | Lempp TJ | Molecular genetics and metabolism | 2007 | PMID: 17113806 |
Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. | Worgan LC | Human mutation | 2006 | PMID: 16281286 |
mut0 methylmalonic acidemia: eleven novel mutations of the methylmalonyl CoA mutase including a deletion-insertion mutation. | Fuchshuber A | Human mutation | 2000 | PMID: 10923046 |
Text-mined citations for rs778702777 ...
HelpRecord last updated May 12, 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.