VCV000218990.13 - ClinVar

NM_000255.4(MMUT):c.1280G>A (p.Gly427Asp)

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.

(7)

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.1280G>A (p.Gly427Asp)

Variation ID: 218990 Accession: VCV000218990.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6p12.3 6: 49451518 (GRCh38) [ NCBI UCSC ] 6: 49419231 (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	Jan 16, 2016	Feb 14, 2024	Jan 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000255.4:c.1280G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000246.2:p.Gly427Asp	missense
NC_000006.12:g.49451518C>T
NC_000006.11:g.49419231C>T
NG_007100.1:g.16622G>A
	P22033:p.Gly427Asp
	NP_000246.1:p.Gly427Asp

... more HGVS ... less HGVS

Protein change

G427D

Other names

Canonical SPDI

NC_000006.12:49451517:C:T

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

ClinGen: CA347873 UniProtKB: P22033#VAR_026621 dbSNP: rs753288303 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 (3)	criteria provided, single submitter	Oct 31, 2018	RCV000203344.9
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 25, 2024	RCV000723412.9
Methylmalonic acidemia	Pathogenic (1)	criteria provided, single submitter	Feb 9, 2017	RCV000588430.1
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency	Pathogenic (1)	no assertion criteria provided	Sep 16, 2020	RCV001271706.1

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 (Feb 09, 2017)	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: SCV000696303.1 First in ClinVar: Mar 20, 2018 Last updated: Mar 20, 2018	Publications: PubMed (2) PubMed: 25750861‚ 25299208 Comment: Variant summary: The MUT c.1280G>A (p.Gly427Asp) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. … (more) Variant summary: The MUT c.1280G>A (p.Gly427Asp) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 4/121440 control chromosomes at a frequency of 0.0000329, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUT variant (0.0024152). This variant has been reported in multiple affected individuals as homozygote as well as compound heterozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893721.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Sep 08, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000330976.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 16281286‚ 23430940 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MUT Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Jan 25, 2024)	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: SCV001204955.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 16281286‚ 25299208‚ 27233228 Comment: This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 427 of the MUT protein … (more) This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 427 of the MUT protein (p.Gly427Asp). This variant is present in population databases (rs753288303, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive methylmalonic acidemia (PMID: 16281286, 25299208, 27233228). ClinVar contains an entry for this variant (Variation ID: 218990). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 30, 2018)	no assertion criteria provided Method: clinical testing	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000798851.2 First in ClinVar: Dec 06, 2016 Last updated: Mar 31, 2019	Publications: PubMed (2) PubMed: 16281286‚ 23430940
Pathogenic (Sep 16, 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: SCV001453054.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
not provided (-)	no classification provided Method: literature only	Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000258504.2 First in ClinVar: Jan 16, 2016 Last updated: Oct 01, 2022 Comment: mut0 enzymatic subtype	Publications: BookShelf: NBK1231 BookShelf: NBK1231

Comment:

Variant summary: The MUT c.1280G>A (p.Gly427Asp) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 4/121440 control chromosomes at a frequency of 0.0000329, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUT variant (0.0024152). This variant has been reported in multiple affected individuals as homozygote as well as compound heterozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 427 of the MUT protein (p.Gly427Asp). This variant is present in population databases (rs753288303, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive methylmalonic acidemia (PMID: 16281286, 25299208, 27233228). ClinVar contains an entry for this variant (Variation ID: 218990). 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 with a positive predictive value of 95%. For these reasons, this variant has been 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
Isolated Methylmalonic Acidemia.	Adam MP	-	2022	PMID: 20301409
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
Mutation analysis of methylmalonyl CoA mutase gene exon 2 in Egyptian families: Identification of 25 novel allelic variants.	Ghoraba DA	Meta gene	2015	PMID: 25750861
Mutation analysis and prenatal diagnosis for three families affected by isolated methylmalonic aciduria.	Kong XD	Genetics and molecular research : GMR	2014	PMID: 25299208
Mutation Profile of the MUT Gene in Chinese Methylmalonic Aciduria Patients.	Liu MY	JIMD reports	2012	PMID: 23430940
Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype.	Worgan LC	Human mutation	2006	PMID: 16281286
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MUT	-	-	-	-

Text-mined citations for rs753288303 ...

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.1280G>A (p.Gly427Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs753288303 ...