VCV000203823.13 - ClinVar

NM_015506.3(MMACHC):c.3G>A (p.Met1Ile)

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.

(5)

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_015506.3(MMACHC):c.3G>A (p.Met1Ile)

Variation ID: 203823 Accession: VCV000203823.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45500335 (GRCh38) [ NCBI UCSC ] 1: 45966007 (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	Sep 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_015506.3:c.3G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056321.2:p.Met1Ile	missense initiator codon variant
NM_001330540.2:c.-220G>A		5 prime UTR
NC_000001.11:g.45500335G>A
NC_000001.10:g.45966007G>A
NG_013378.1:g.5152G>A

... more HGVS ... less HGVS

Protein change

M1I

Other names

Canonical SPDI

NC_000001.11:45500334:G:A

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

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Links

dbSNP: rs779893448 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.
MMACHC		-	-	GRCh38 GRCh37	527	620

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.
Cobalamin C disease	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 24, 2023	RCV000664762.11
Methylmalonic acidemia with homocystinuria cblC	Pathogenic (1)	no assertion criteria provided	Sep 16, 2020	RCV001272216.1

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 (Dec 15, 2016)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Cobalamin C disease Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000788772.2 First in ClinVar: Aug 05, 2018 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 16311595
Pathogenic (Oct 29, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Methylmalonic acidemia with homocystinuria Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000919674.2 First in ClinVar: Jun 02, 2019 Last updated: Sep 03, 2023	Publications: PubMed (2) PubMed: 18164228‚ 16311595 Comment: Variant summary: MMACHC c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded … (more) Variant summary: MMACHC c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246258 control chromosomes (gnomAD). c.3G>A has been reported in the literature in multiple individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria)(Lerner-Ellis_2006, Nogueira_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cobalamin C disease Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004178125.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Sep 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cobalamin C disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001402079.6 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 16311595‚ 18164228‚ 19760748 Comment: This sequence change affects the initiator methionine of the MMACHC mRNA. The next in-frame methionine is located at codon 58. This variant is present in … (more) This sequence change affects the initiator methionine of the MMACHC mRNA. The next in-frame methionine is located at codon 58. This variant is present in population databases (rs779893448, gnomAD 0.003%). Disruption of the initiator codon has been observed in individuals with combined methylmalonic aciduria and homocystinuria (PMID: 16311595, 18164228, 19760748). ClinVar contains an entry for this variant (Variation ID: 203823). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Methylmalonic aciduria with homocystinuria cblC type Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453985.2 First in ClinVar: Jan 02, 2021 Last updated: Sep 03, 2023

Comment:

Variant summary: MMACHC c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246258 control chromosomes (gnomAD). c.3G>A has been reported in the literature in multiple individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria)(Lerner-Ellis_2006, Nogueira_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change affects the initiator methionine of the MMACHC mRNA. The next in-frame methionine is located at codon 58. This variant is present in population databases (rs779893448, gnomAD 0.003%). Disruption of the initiator codon has been observed in individuals with combined methylmalonic aciduria and homocystinuria (PMID: 16311595, 18164228, 19760748). ClinVar contains an entry for this variant (Variation ID: 203823). 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
Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC).	Richard E	Human mutation	2009	PMID: 19760748
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 rs779893448 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_015506.3(MMACHC):c.3G>A (p.Met1Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs779893448 ...