ClinVar Genomic variation as it relates to human health
NM_015506.3(MMACHC):c.609G>A (p.Trp203Ter)
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.609G>A (p.Trp203Ter)
Variation ID: 30800 Accession: VCV000030800.54
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45508975 (GRCh38) [ NCBI UCSC ] 1: 45974647 (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 15, 2018 Jun 23, 2024 Mar 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015506.3:c.609G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056321.2:p.Trp203Ter nonsense NM_001330540.2:c.438G>A NP_001317469.1:p.Trp146Ter nonsense NC_000001.11:g.45508975G>A NC_000001.10:g.45974647G>A NG_013378.1:g.13792G>A - Protein change
- W203*, W146*
- Other names
- -
- Canonical SPDI
- NC_000001.11:45508974:G: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00010
1000 Genomes Project 30x 0.00016
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 (14) |
criteria provided, multiple submitters, no conflicts
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Mar 28, 2024 | RCV000023785.26 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 25, 2017 | RCV000756343.12 | |
not provided (1) |
no classification provided
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- | RCV002513204.4 | |
Pathogenic (1) |
no assertion criteria provided
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Sep 16, 2020 | RCV001275215.4 |
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
(Jul 13, 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: SCV000699402.1
First in ClinVar: Jan 15, 2018 Last updated: Jan 15, 2018 |
Comment:
Variant summary: The MMACHC c.609G>A (p.Trp203X) 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.609G>A (p.Trp203X) 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. One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/121366 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant has been reported in numerous affected individuals in the homozygous and compound heterozygous state, and there is evidence the variant may be a founder mutation in the Chinese population (Lerner-Ellis_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Jul 25, 2017)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000884123.1
First in ClinVar: Feb 18, 2019 Last updated: Feb 18, 2019 |
Comment:
The p.Trp203Ter variant creates a termination codon in the MMACHC protein at codon 203 in exon 4 which is predicted to result in a truncated … (more)
The p.Trp203Ter variant creates a termination codon in the MMACHC protein at codon 203 in exon 4 which is predicted to result in a truncated or absent protein product. In a cohort of 204 individuals suspected with inborn errors in cobalamin metabolism, the p.Trp203Ter was identified in the MMACHC gene from 7 individuals with pathogenic bi-allelic variants, including 5 homozygotes (Lerner-Ellis et. al. 2006). Furthermore, the p.Trp203Ter was observed in 52 out of 71 Chinese patients, including 15 homozygotes with elevated methylmalonic aciduria (MMA) and homocystinuria (HC), whereby haplotype analysis determined that it may have been caused by a founder effect in this population (Liu et. al. 2010). This variant is reported in ClinVar (Variation ID: 30800) as pathogenic. It is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.004 percent (identified on 10 out of 246,224 chromosomes). Based on these observations the p.Trp203Ter is pathogenic. (less)
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Pathogenic
(Feb 02, 2022)
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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: SCV000894028.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 09, 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: SCV000949474.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Trp203*) 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.Trp203*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 80 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs587776889, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with MMACHC-related conditions (PMID: 16311595, 20631720, 23954310, 25772322, 27383490, 28327205). ClinVar contains an entry for this variant (Variation ID: 30800). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Mar 28, 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: SCV001162918.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
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Pathogenic
(Mar 17, 2017)
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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: SCV000790396.1
First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018 |
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Pathogenic
(May 13, 2021)
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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 Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University
Accession: SCV001622425.1
First in ClinVar: May 20, 2021 Last updated: May 20, 2021 |
Clinical Features:
Global developmental delay (present) , Intellectual disability (present) , Microcephaly (present) , Craniosynostosis syndrome (present) , Hydrocephalus (present)
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Pathogenic
(Feb 28, 2020)
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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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Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital
Accession: SCV001739475.1
First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021 |
Number of individuals with the variant: 1
Age: 0-9 years
Sex: female
Ethnicity/Population group: East asia
Geographic origin: China
Testing laboratory: Liwei's Lab
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Pathogenic
(Oct 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: yes
Allele origin:
maternal
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3billion
Accession: SCV002012349.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000441, PM2). he variant was observed in trans with a pathogenic variant (NM_015506.2: c.394C>T) as compound heterozygous (3billion dataset, PM3). The variant has been reported multiple times as an established pathogenic variant (ClinVar ID: VCV000030800.12). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Seizure (present) , Inborn organic aciduria (present) , Delayed speech and language development (present) , Methylmalonic aciduria (present) , Delayed gross motor development (present) , … (more)
Seizure (present) , Inborn organic aciduria (present) , Delayed speech and language development (present) , Methylmalonic aciduria (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Intellectual disability (present) (less)
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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: SCV004178208.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: yes
Allele origin:
maternal
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Precision Medicine Center, Zhengzhou University
Accession: SCV004218488.1
First in ClinVar: Jun 23, 2024 Last updated: Jun 23, 2024 |
Comment:
PVS1,PM2_p,PM3
Sex: female
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Pathogenic
(-)
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no assertion criteria provided
Method: case-control
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Cobalamin C disease
Affected status: yes
Allele origin:
inherited
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Biochemistry Laboratory of CDMU, Chengde Medical University
Accession: SCV000899210.1
First in ClinVar: May 02, 2019 Last updated: May 02, 2019 |
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Pathogenic
(Apr 23, 2020)
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no assertion criteria provided
Method: research
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Methylmalonic acidemia with homocystinuria
Affected status: yes
Allele origin:
germline
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Neurology Department, Peking University First Hospital
Accession: SCV001423143.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
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Pathogenic
(Sep 01, 2010)
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no assertion criteria provided
Method: literature only
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METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000045076.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 13, 2021 |
Comment on evidence:
In Chinese patients with methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400), Liu et al. (2010) identified a 609G-A transition in exon 4 of the … (more)
In Chinese patients with methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400), Liu et al. (2010) identified a 609G-A transition in exon 4 of the MMACHC gene, resulting in a trp203-to-ter (W203X) substitution. This allele was the most common mutation found among 79 unrelated patients, accounting for 48.1% of mutant alleles. Fifteen patients who were homozygous for the mutation showed an early-onset phenotype, with 3 showing onset before age 4 years. Haplotype analysis suggested a founder effect. In a molecular analysis of 70 Chinese individuals with MAHCC, He et al. (2020) found that the W203X mutation accounted for 62.9% of the identified mutations. Twenty-nine patients were homozygous for the mutation. (less)
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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: SCV001460139.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Cobalamin C disease
Affected status: unknown
Allele origin:
paternal
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Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University
Accession: SCV003838960.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
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not provided
(-)
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no classification provided
Method: literature only
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Disorders of Intracellular Cobalamin Metabolism
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV003354480.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
Common in people of Chinese ancestry.
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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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Disorders of Intracellular Cobalamin Metabolism. | Adam MP | - | 2021 | PMID: 20301503 |
Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency. | He R | Neurology | 2020 | PMID: 32943488 |
Combined methylmalonic acidemia and homocysteinemia presenting predominantly with late-onset diffuse lung disease: a case series of four patients. | Liu J | Orphanet journal of rare diseases | 2017 | PMID: 28327205 |
Report - Report on the heterozygosis mutations of c.567dupT, p.(Ile190Tyrfs*13) of MMACHC gene in 1 Child patient with methylmalonic academia. | Liu K | Pakistan journal of pharmaceutical sciences | 2016 | PMID: 27383490 |
Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level. | Ahrens-Nicklas RC | JIMD reports | 2015 | PMID: 25772322 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
Neurologic and neurodevelopmental phenotypes in young children with early-treated combined methylmalonic acidemia and homocystinuria, cobalamin C type. | Weisfeld-Adams JD | Molecular genetics and metabolism | 2013 | PMID: 23954310 |
Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria. | Liu MY | Journal of human genetics | 2010 | PMID: 20631720 |
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 rs587776889 ...
HelpRecord last updated Jun 23, 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.