VCV000554278.8 - ClinVar

NM_000255.4(MMUT):c.1287C>G (p.Tyr429Ter)

Germline

Classification

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.

(4)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000255.4(MMUT):c.1287C>G (p.Tyr429Ter)

Variation ID: 554278 Accession: VCV000554278.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p12.3 6: 49451511 (GRCh38) [ NCBI UCSC ] 6: 49419224 (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	Aug 5, 2018	Feb 14, 2024	May 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000255.4:c.1287C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000246.2:p.Tyr429Ter	nonsense
NC_000006.12:g.49451511G>C
NC_000006.11:g.49419224G>C
NG_007100.1:g.16629C>G

Protein change

Y429*

Other names

Canonical SPDI

NC_000006.12:49451510:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

dbSNP: rs1346775255 VarSome

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
Gene	OMIM	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.
MMUT		-	-	GRCh38 GRCh37	1080	1093

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.
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency	Pathogenic (1)	criteria provided, single submitter	Oct 11, 2017	RCV000669883.3
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency	Pathogenic (1)	no assertion criteria provided	Sep 10, 2020	RCV001830442.1
not provided	Pathogenic (1)	criteria provided, single submitter	May 22, 2023	RCV001376628.4
Methylmalonic acidemia	Pathogenic (1)	criteria provided, single submitter	Jul 25, 2022	RCV002282308.1

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 (May 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001229452.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 15781192‚ 16281286 Comment: This sequence change creates a premature translational stop signal (p.Tyr429) in the MUT gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Tyr429) in the MUT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). This variant is present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with cobalamin nonresponsive methylmalonic acidemia (PMID: 16281286). ClinVar contains an entry for this variant (Variation ID: 554278). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 25, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Methylmalonic acidemia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002570548.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (2) PubMed: 16281286‚ 27233228 Comment: Variant summary: MUT c.1287C>G (p.Tyr429X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: MUT c.1287C>G (p.Tyr429X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251238 control chromosomes. c.1287C>G has been reported in the literature in individuals affected with Methylmalonic Acidemia (eg. Worgan_2006, Chu_2016). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Oct 11, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000794679.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 16281286‚ 27233228
Pathogenic (Sep 10, 2020)	no assertion criteria provided Method: clinical testing	Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002077377.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Comment:

This sequence change creates a premature translational stop signal (p.Tyr429*) in the MUT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). This variant is present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with cobalamin nonresponsive methylmalonic acidemia (PMID: 16281286). ClinVar contains an entry for this variant (Variation ID: 554278). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: MUT c.1287C>G (p.Tyr429X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251238 control chromosomes. c.1287C>G has been reported in the literature in individuals affected with Methylmalonic Acidemia (eg. Worgan_2006, Chu_2016). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Next generation sequencing of patients with mut methylmalonic aciduria: Validation of somatic cell studies and identification of 16 novel mutations.	Chu J	Molecular genetics and metabolism	2016	PMID: 27233228
Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype.	Worgan LC	Human mutation	2006	PMID: 16281286
Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants.	Martínez MA	Molecular genetics and metabolism	2005	PMID: 15781192

Text-mined citations for rs1346775255 ...

These 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 08, 2024

ClinVar Genomic variation as it relates to human health

NM_000255.4(MMUT):c.1287C>G (p.Tyr429Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1346775255 ...