VCV000203814.15 - ClinVar

NM_172250.3(MMAA):c.387C>A (p.Tyr129Ter)

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.

(8)

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_172250.3(MMAA):c.387C>A (p.Tyr129Ter)

Variation ID: 203814 Accession: VCV000203814.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q31.21 4: 145639526 (GRCh38) [ NCBI UCSC ] 4: 146560678 (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	Oct 9, 2016	Jun 17, 2024	Jan 27, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_172250.3:c.387C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_758454.1:p.Tyr129Ter	nonsense
NC_000004.12:g.145639526C>A
NC_000004.11:g.146560678C>A
NG_007536.2:g.45485C>A
LRG_1301:g.45485C>A
LRG_1301t1:c.387C>A	LRG_1301p1:p.Tyr129Ter

... more HGVS ... less HGVS

Protein change

Y129*

Other names

Canonical SPDI

NC_000004.12:145639525:C: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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Links

ClinGen: CA312703 dbSNP: rs796051992 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.
MMAA		-	-	GRCh38 GRCh37	550	586

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.
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 6, 2016	RCV000186011.2
Methylmalonic aciduria, cblA type	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 27, 2024	RCV000671866.14
Methylmalonic acidemia	Pathogenic (1)	criteria provided, single submitter	May 9, 2021	RCV001420837.1
MMAA-related disorder	Pathogenic (1)	criteria provided, single submitter	Jan 23, 2023	RCV003401020.5

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 (Jan 04, 2018)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Methylmalonic aciduria, cblA type Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000796896.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 26270765‚ 15523652
Pathogenic (Jun 06, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000238973.11 First in ClinVar: Jul 18, 2015 Last updated: Oct 09, 2016	Comment: The Y129X nonsense variant in the MMAA gene has been reported previously in association with methylmalonic acidemia (MMA), cblA type in an individual who was … (more) The Y129X nonsense variant in the MMAA gene has been reported previously in association with methylmalonic acidemia (MMA), cblA type in an individual who was homozygous for the Y129X variant (Lerner-Ellis et al., 2004). This variant is predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay. (less)
Pathogenic (May 09, 2021)	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: SCV001623231.1 First in ClinVar: May 23, 2021 Last updated: May 23, 2021	Publications: PubMed (2) PubMed: 15523652‚ 32754920 Comment: Variant summary: MMAA c.387C>A (p.Tyr129X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: MMAA c.387C>A (p.Tyr129X) 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 allele was found at a frequency of 8e-06 in 250652 control chromosomes. c.387C>A has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (example, Lerner-Ellis_2004, Horster_2021). These data indicate that the variant is very likely to be associated with disease. 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 (Jan 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MMAA-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004119870.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The MMAA c.387C>A variant is predicted to result in premature protein termination (p.Tyr129). This variant has been reported, in the homozygous state or heterozygous state … (more) The MMAA c.387C>A variant is predicted to result in premature protein termination (p.Tyr129). This variant has been reported, in the homozygous state or heterozygous state with a second causative MMAA variant, in at least two cblA type methylmalonic acidemia patients (MMA) (Lerner-Ellis et al 2004. PubMed ID: 15523652; Table S1 - Manoli et al. 2016. PubMed ID: 26270765; Hörster et al. 2020. PubMed ID: 32754920). Other loss-of-function variants surrounding this region have also been reported to be causative for MMA. This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-146560678-C-A). Nonsense variants in MMAA are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. (less)
Pathogenic (Jan 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Methylmalonic aciduria, cblA type Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003821651.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jan 27, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Methylmalonic aciduria, cblA type Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001582543.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 15523652‚ 15781192‚ 25959030 Comment: This sequence change creates a premature translational stop signal (p.Tyr129) in the MMAA gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Tyr129) in the MMAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192). This variant is present in population databases (rs796051992, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria cobalamin A type (PMID: 15523652, 25959030). ClinVar contains an entry for this variant (Variation ID: 203814). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Methylmalonic aciduria, cblA type Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004193098.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Methylmalonic aciduria cblA type Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001452008.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

The Y129X nonsense variant in the MMAA gene has been reported previously in association with methylmalonic acidemia (MMA), cblA type in an individual who was homozygous for the Y129X variant (Lerner-Ellis et al., 2004). This variant is predicted to cause loss of normal protein function either through premature protein truncation or nonsense-mediated mRNA decay.

Comment:

Variant summary: MMAA c.387C>A (p.Tyr129X) 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 allele was found at a frequency of 8e-06 in 250652 control chromosomes. c.387C>A has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (example, Lerner-Ellis_2004, Horster_2021). These data indicate that the variant is very likely to be associated with disease. 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.

Comment:

The MMAA c.387C>A variant is predicted to result in premature protein termination (p.Tyr129*). This variant has been reported, in the homozygous state or heterozygous state with a second causative MMAA variant, in at least two cblA type methylmalonic acidemia patients (MMA) (Lerner-Ellis et al 2004. PubMed ID: 15523652; Table S1 - Manoli et al. 2016. PubMed ID: 26270765; Hörster et al. 2020. PubMed ID: 32754920). Other loss-of-function variants surrounding this region have also been reported to be causative for MMA. This variant is reported in 0.0057% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-146560678-C-A). Nonsense variants in MMAA are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Tyr129*) in the MMAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192). This variant is present in population databases (rs796051992, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria cobalamin A type (PMID: 15523652, 25959030). ClinVar contains an entry for this variant (Variation ID: 203814). 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
Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut.	Hörster F	Journal of inherited metabolic disease	2021	PMID: 32754920
A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias.	Manoli I	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26270765
Delineating the spectrum of impairments, disabilities, and rehabilitation needs in methylmalonic acidemia (MMA).	Ktena YP	American journal of medical genetics. Part A	2015	PMID: 25959030
Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants.	Martínez MA	Molecular genetics and metabolism	2005	PMID: 15781192
Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism.	Lerner-Ellis JP	Human mutation	2004	PMID: 15523652

Text-mined citations for rs796051992 ...

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_172250.3(MMAA):c.387C>A (p.Tyr129Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs796051992 ...