NM_015506.3(MMACHC):c.384del (p.Tyr129fs) AND Cobalamin C disease

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Oct 18, 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:: RCV000674328.8

Allele description [Variation Report for NM_015506.3(MMACHC):c.384del (p.Tyr129fs)]

NM_015506.3(MMACHC):c.384del (p.Tyr129fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

1p34.1

Genomic location:

Preferred name:

NM_015506.3(MMACHC):c.384del (p.Tyr129fs)

HGVS:

NC_000001.11:g.45508319del
NG_013378.1:g.13136del
NM_001330540.2:c.213del
NM_015506.3:c.384delMANE SELECT
NP_001317469.1:p.Tyr72fs
NP_056321.2:p.Tyr129fs
NC_000001.10:g.45973991del
NM_015506.2:c.384delC

Protein change:

Y129fs

Links:

dbSNP: rs1347498294

NCBI 1000 Genomes Browser:

rs1347498294

Molecular consequence:

NM_001330540.2:c.213del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_015506.3:c.384del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000799650	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (May 1, 2018)	unknown	clinical testing	Citation Link,
SCV002132285	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16311595, 19767224, 30157807, 28492532
SCV004178161	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004193165	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 18, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

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

High prevalence of structural heart disease in children with cblC-type methylmalonic aciduria and homocystinuria.

Profitlich LE, Kirmse B, Wasserstein MP, Diaz GA, Srivastava S.

Mol Genet Metab. 2009 Dec;98(4):344-8. doi: 10.1016/j.ymgme.2009.07.017. Epub 2009 Aug 12.

PubMed [citation]

PMID:: 19767224

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000799650.1

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

#	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 Invitae, SCV002132285.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant has not been reported in the literature in individuals affected with MMACHC-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Tyr129Thrfs*35) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 154 amino acid(s) of the MMACHC protein. ClinVar contains an entry for this variant (Variation ID: 558102). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MMACHC protein in which other variant(s) (p.Tyr222*) have been determined to be pathogenic (PMID: 16311595, 19767224, 30157807). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing.

#	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, SCV004178161.1

#	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

From Baylor Genetics, SCV004193165.1

#	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

Last Updated: Feb 28, 2024

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