NM_015506.3(MMACHC):c.90G>A (p.Trp30Ter) AND Cobalamin C disease

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 25, 2024
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:: RCV000671638.9

Allele description [Variation Report for NM_015506.3(MMACHC):c.90G>A (p.Trp30Ter)]

NM_015506.3(MMACHC):c.90G>A (p.Trp30Ter)

Gene:

MMACHC:metabolism of cobalamin associated C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_015506.3(MMACHC):c.90G>A (p.Trp30Ter)

HGVS:

NC_000001.11:g.45507364G>A
NG_013378.1:g.12181G>A
NM_001330540.2:c.-82G>A
NM_015506.3:c.90G>AMANE SELECT
NP_056321.2:p.Trp30Ter
NC_000001.10:g.45973036G>A
NM_015506.2:c.90G>A

Protein change:

W30*

Links:

dbSNP: rs771673343

NCBI 1000 Genomes Browser:

rs771673343

Molecular consequence:

NM_001330540.2:c.-82G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_015506.3:c.90G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Cobalamin C disease
Synonyms:: Cobalamin-C methylmalonic acidemia and homocystinuria; Methylmalonic acidemia and homocystinuria cblC type; Methylmalonic aciduria and homocystinuria, Vitamin B12-responsive; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010184; MedGen: C1848561; Orphanet: 26; Orphanet: 79282; OMIM: 277400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000796631	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Dec 28, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001162893	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 15, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002238945	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16311595, 19760748, 28492532
SCV004037958	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 17, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004178130	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type.

Lerner-Ellis JP, Tirone JC, Pawelek PD, Doré C, Atkinson JL, Watkins D, Morel CF, Fujiwara TM, Moras E, Hosack AR, Dunbar GV, Antonicka H, Forgetta V, Dobson CM, Leclerc D, Gravel RA, Shoubridge EA, Coulton JW, Lepage P, Rommens JM, Morgan K, Rosenblatt DS.

Nat Genet. 2006 Jan;38(1):93-100. Epub 2005 Nov 27. Erratum in: Nat Genet. 2006 Aug;38(8):957.

PubMed [citation]

PMID:: 16311595

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000796631.1

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

#	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 Baylor Genetics, SCV001162893.2

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002238945.3

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

Description

This sequence change creates a premature translational stop signal (p.Trp30*) in the MMACHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMACHC are known to be pathogenic (PMID: 16311595). This variant is present in population databases (rs771673343, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 19760748). ClinVar contains an entry for this variant (Variation ID: 555758). For these reasons, this variant has been classified as Pathogenic.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004037958.1

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

Description

Variant summary: MMACHC c.90G>A (p.Trp30X) 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. The variant allele was found at a frequency of 4e-06 in 249290 control chromosomes (gnomAD). c.90G>A has been reported in the literature in individuals affected with Methylmalonic Acidemia With Homocystinuria (Richard_2009). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 19760748). Two ClinVar submitters have assessed this variant since 2014: one classified the variant as likely pathogenic and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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 Genome-Nilou Lab, SCV004178130.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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