NM_000255.4(MMUT):c.682C>T (p.Arg228Ter) AND Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Feb 23, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000666877.7

Allele description [Variation Report for NM_000255.4(MMUT):c.682C>T (p.Arg228Ter)]

NM_000255.4(MMUT):c.682C>T (p.Arg228Ter)

Gene:

MMUT:methylmalonyl-CoA mutase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p12.3

Genomic location:

Preferred name:

NM_000255.4(MMUT):c.682C>T (p.Arg228Ter)

HGVS:

NC_000006.12:g.49457762G>A
NG_007100.1:g.10378C>T
NM_000255.4:c.682C>TMANE SELECT
NP_000246.2:p.Arg228Ter
NC_000006.11:g.49425475G>A
NM_000255.3:c.682C>T
p.R228X

Protein change:

R228*

Links:

dbSNP: rs200596762

NCBI 1000 Genomes Browser:

rs200596762

Molecular consequence:

NM_000255.4:c.682C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
Synonyms:: Methylmalonic aciduria, mut type
Identifiers:: MONDO: MONDO:0009612; MedGen: C1855114; OMIM: 251000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000791244	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (May 15, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17470278, 19088183, 27233228 Citation Link,
SCV000916152	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Sep 27, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15643616, 27233228, 26790480 Citation Link,
SCV003807049	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003841455	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15643616, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Adenoviral-mediated correction of methylmalonyl-CoA mutase deficiency in murine fibroblasts and human hepatocytes.

Chandler RJ, Tsai MS, Dorko K, Sloan J, Korson M, Freeman R, Strom S, Venditti CP.

BMC Med Genet. 2007 Apr 30;8:24.

PubMed [citation]

PMID:: 17470278
PMCID:: PMC1876207

Mitochondrial dysfunction in mut methylmalonic acidemia.

Chandler RJ, Zerfas PM, Shanske S, Sloan J, Hoffmann V, DiMauro S, Venditti CP.

FASEB J. 2009 Apr;23(4):1252-61. doi: 10.1096/fj.08-121848. Epub 2008 Dec 16.

PubMed [citation]

PMID:: 19088183
PMCID:: PMC2660647

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000791244.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000916152.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Across a selection of the available literature, the MUT c.682C>T (p.Arg228Ter) variant has been identified in a homozygous state in at least one proband and in a compound heterozygous state in at least eleven probands with methylmalonic academia (Acquaviva et al. 2005; Chu et al. 2016; Harrington et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000209 in the Latino population of the Genome Aggregation Database. Based on the evidence and the potential impact of stop-gained variants, the p.Arg228Ter variant is classified as pathogenic for methylmalonic acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV003807049.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated, PM3 moderated

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From 3billion, SCV003841455.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). This variant was 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. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000203855 / PMID: 15643616). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 24, 2023

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