ClinVar Genomic variation as it relates to human health
NM_015506.3(MMACHC):c.666C>A (p.Tyr222Ter)
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_015506.3(MMACHC):c.666C>A (p.Tyr222Ter)
Variation ID: 496436 Accession: VCV000496436.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45509032 (GRCh38) [ NCBI UCSC ] 1: 45974704 (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 17, 2018 Jun 17, 2024 Mar 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015506.3:c.666C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056321.2:p.Tyr222Ter nonsense NM_001330540.2:c.495C>A NP_001317469.1:p.Tyr165Ter nonsense NC_000001.11:g.45509032C>A NC_000001.10:g.45974704C>A NG_013378.1:g.13849C>A - Protein change
- Y222*, Y165*
- Other names
- -
- Canonical SPDI
- NC_000001.11:45509031:C:A
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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 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
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. |
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LOC129930446 | - | - | - | GRCh38 | - | 67 |
MMACHC | - | - |
GRCh38 GRCh37 |
525 | 617 |
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. |
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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Mar 27, 2024 | RCV000590695.16 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 16, 2020 | RCV001275219.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2022 | RCV002473068.1 |
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. |
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Pathogenic
(Aug 21, 2017)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699404.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The MMACHC c.666C>A (p.Tyr222X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense … (more)
Variant summary: The MMACHC c.666C>A (p.Tyr222X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. MutationTaster predicts a damaging outcome for this variant. This variant was found in the large control database ExAC and control cohorts from the literature at a frequency of 0.0000496 (6/120940 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant has been identified in numerous patients who were homozygous or compound heterozygous with a known mutation, several of whom were reported as having an early onset of disease. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Dec 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761665.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Dec 21, 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: SCV002770008.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
Nonsense variant predicted to result in protein truncation, as the last 61 amino acids are lost, and other loss-of-function variants have been reported downstream in … (more)
Nonsense variant predicted to result in protein truncation, as the last 61 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31470807, 31503356, 31998365, 22447314, 32943488, 31589614, 26825575, 18164228, 19370762, 34215320, 33691766, 34102818, 35361390, 28481040, 16311595, 33473346, 30157807) (less)
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Pathogenic
(Sep 17, 2021)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002780203.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004178224.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Dec 17, 2023)
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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: SCV001225598.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr222*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Tyr222*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs201266016, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria and homocystinuria (PMID: 16311595, 19767224, 30157807). ClinVar contains an entry for this variant (Variation ID: 496436). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 27, 2024)
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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: SCV004193169.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(May 15, 2017)
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no assertion criteria provided
Method: clinical testing
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Cobalamin C disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000791247.2
First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Methylmalonic aciduria with homocystinuria cblC type
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001460143.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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 |
Ophthalmic Manifestations and Long-Term Visual Outcomes in Patients with Cobalamin C Deficiency. | Brooks BP | Ophthalmology | 2016 | PMID: 26825575 |
Neonatal atypical hemolytic uremic syndrome due to methylmalonic aciduria and homocystinuria. | Menni F | Pediatric nephrology (Berlin, Germany) | 2012 | PMID: 22447314 |
High prevalence of structural heart disease in children with cblC-type methylmalonic aciduria and homocystinuria. | Profitlich LE | Molecular genetics and metabolism | 2009 | PMID: 19767224 |
Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. | Lerner-Ellis JP | Human mutation | 2009 | PMID: 19370762 |
Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type. | Nogueira C | Molecular genetics and metabolism | 2008 | PMID: 18164228 |
Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. | Lerner-Ellis JP | Nature genetics | 2006 | PMID: 16311595 |
Text-mined citations for rs201266016 ...
HelpRecord last updated Jun 17, 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.