ClinVar Genomic variation as it relates to human health
NM_015506.3(MMACHC):c.616C>T (p.Arg206Trp)
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.
Pathogenic(2); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_015506.3(MMACHC):c.616C>T (p.Arg206Trp)
Variation ID: 203832 Accession: VCV000203832.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45508982 (GRCh38) [ NCBI UCSC ] 1: 45974654 (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 May 25, 2017 Feb 14, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015506.3:c.616C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056321.2:p.Arg206Trp missense NM_001330540.2:c.445C>T NP_001317469.1:p.Arg149Trp missense NC_000001.11:g.45508982C>T NC_000001.10:g.45974654C>T NG_013378.1:g.13799C>T Q9Y4U1:p.Arg206Trp - Protein change
- R206W, R149W
- Other names
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- Canonical SPDI
- NC_000001.11:45508981: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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0.00020 (G)
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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) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
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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LOC129930446 | - | - | - | GRCh38 | - | 67 |
MMACHC | - | - |
GRCh38 GRCh37 |
521 | 612 |
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
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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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 18, 2024 | RCV000490478.11 |
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
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
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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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Uncertain significance
(Mar 18, 2016)
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criteria provided, single submitter
Method: reference population
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Cobalamin C disease
Affected status: unknown
Allele origin:
germline
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Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center
Accession: SCV000267397.1
First in ClinVar: May 25, 2017 Last updated: May 25, 2017 |
Number of individuals with the variant: 1
Age: 40-69 years
Ethnicity/Population group: East Asian
Geographic origin: South Korean
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Likely pathogenic
(Jan 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000800803.1
First in ClinVar: May 25, 2017 Last updated: May 25, 2017 |
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Pathogenic
(Jan 18, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001372575.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 206 of the MMACHC protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 206 of the MMACHC protein (p.Arg206Trp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 16311595, 20610126, 20631720, 26149271). 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: 203832). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MMACHC protein function. This variant disrupts the p.Arg206 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30157807). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004193163.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Sep 02, 2020)
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no assertion criteria provided
Method: clinical testing
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Methylmalonic aciduria and homocystinuria cblC type
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002089550.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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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Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria. | Hu S | BMC medical genetics | 2018 | PMID: 30157807 |
Prenatal diagnosis using genetic sequencing and identification of a novel mutation in MMACHC. | Zong Y | BMC medical genetics | 2015 | PMID: 26149271 |
Clinical presentation and outcome in a series of 88 patients with the cblC defect. | Fischer S | Journal of inherited metabolic disease | 2014 | PMID: 24599607 |
Interaction between methionine synthase isoforms and MMACHC: characterization in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia. | Fofou-Caillierez MB | Human molecular genetics | 2013 | PMID: 23825108 |
Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria. | Liu MY | Journal of human genetics | 2010 | PMID: 20631720 |
Early onset methylmalonic aciduria and homocystinuria cblC type with demyelinating neuropathy. | Frattini D | Pediatric neurology | 2010 | PMID: 20610126 |
Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. | Lerner-Ellis JP | Human mutation | 2009 | PMID: 19370762 |
Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. | Lerner-Ellis JP | Nature genetics | 2006 | PMID: 16311595 |
Text-mined citations for rs538023671 ...
HelpRecord last updated Feb 20, 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.