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NM_015506.3(MMACHC):c.328_331del (p.Asn110fs) AND Cobalamin C disease

Germline classification:
Pathogenic (7 submissions)
Last evaluated:
Feb 23, 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:
RCV000531346.19

Allele description [Variation Report for NM_015506.3(MMACHC):c.328_331del (p.Asn110fs)]

NM_015506.3(MMACHC):c.328_331del (p.Asn110fs)

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.328_331del (p.Asn110fs)
HGVS:
  • NC_000001.10:g.45973933_45973936del
  • NC_000001.11:g.45508263_45508266del
  • NG_013378.1:g.13080_13083del
  • NM_001330540.2:c.157_160del
  • NM_015506.3:c.328_331delMANE SELECT
  • NP_001317469.1:p.Asn53fs
  • NP_056321.2:p.Asn110fs
  • NC_000001.10:g.45973933_45973936del
  • NC_000001.10:g.45973935_45973938del
  • NC_000001.10:g.45973935_45973938delAACC
  • NM_015506.2:c.328_331del
  • NM_015506.2:c.328_331delAACC
  • NM_015506.3:c.328_331delAACCMANE SELECT
  • p.N110DfsX13
Protein change:
N110fs
Links:
dbSNP: rs796052000
NCBI 1000 Genomes Browser:
rs796052000
Molecular consequence:
  • NM_001330540.2:c.157_160del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_015506.3:c.328_331del - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000640287Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 11, 2024)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000699396Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Apr 12, 2016)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001132249Counsyl
no assertion criteria provided
Pathogenic
(Mar 16, 2017)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001162898Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 23, 2024)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002017509Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 9, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002811620Fulgent Genetics, Fulgent Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Dec 2, 2021)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004178152Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Apr 11, 2023)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Neurologic and neurodevelopmental phenotypes in young children with early-treated combined methylmalonic acidemia and homocystinuria, cobalamin C type.

Weisfeld-Adams JD, Bender HA, Miley-Åkerstedt A, Frempong T, Schrager NL, Patel K, Naidich TP, Stein V, Spat J, Towns S, Wasserstein MP, Peter I, Frank Y, Diaz GA.

Mol Genet Metab. 2013 Nov;110(3):241-7. doi: 10.1016/j.ymgme.2013.07.018. Epub 2013 Jul 25.

PubMed [citation]
PMID:
23954310

Long-term visual outcome of methylmalonic aciduria and homocystinuria, cobalamin C type.

Gizicki R, Robert MC, Gómez-López L, Orquin J, Decarie JC, Mitchell GA, Roy MS, Ospina LH.

Ophthalmology. 2014 Jan;121(1):381-386. doi: 10.1016/j.ophtha.2013.08.034. Epub 2013 Oct 11.

PubMed [citation]
PMID:
24126030
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000640287.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Asn110Aspfs*13) 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 (rs777767443, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria and homocystinuria, cobalamin C (cblC) type (PMID: 16311595, 19370762, 23954310, 24126030). ClinVar contains an entry for this variant (Variation ID: 203835). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699396.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

Variant summary: The c.328_331delAACC variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein, which is a commonly known mechanism for disease. Truncations downstream of this position have also been associated with CBLC phenotype (e.g. p.Arg132X). One in-silico tool predicts damaging outcome for this variant. This variant is not found in approximately120716 control chromosomes from the large and broad populations of ExAC. This variant has been reported in several patients with CBLC. Multiple reputable databases and one clinical lab has classified this variant as pathogenic. Taken together, this variant has been classified as a Disease Variant/Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV001132249.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001162898.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Revvity Omics, Revvity, SCV002017509.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Fulgent Genetics, Fulgent Genetics, SCV002811620.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Genome-Nilou Lab, SCV004178152.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024