NM_015506.3(MMACHC):c.616C>T (p.Arg206Trp) AND Cobalamin C disease

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Pathogenic(1);Uncertain significance(1) (Last evaluated: Oct 16, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000490478.3

Allele description [Variation Report for NM_015506.3(MMACHC):c.616C>T (p.Arg206Trp)]

NM_015506.3(MMACHC):c.616C>T (p.Arg206Trp)

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.616C>T (p.Arg206Trp)
HGVS:
  • NC_000001.11:g.45508982C>T
  • NG_013378.1:g.13799C>T
  • NM_001330540.2:c.445C>T
  • NM_015506.3:c.616C>TMANE SELECT
  • NP_001317469.1:p.Arg149Trp
  • NP_056321.2:p.Arg206Trp
  • NC_000001.10:g.45974654C>T
  • NM_015506.2:c.616C>T
  • Q9Y4U1:p.Arg206Trp
Protein change:
R149W
Links:
UniProtKB: Q9Y4U1#VAR_024783; dbSNP: rs538023671
NCBI 1000 Genomes Browser:
rs538023671
Molecular consequence:
  • NM_001330540.2:c.445C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015506.3:c.616C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cobalamin C disease (MAHCC)
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
SCV000267397Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Centercriteria provided, single submitter
Uncertain significance
(Mar 18, 2016)
germlinereference population

PubMed (3)
[See all records that cite these PMIDs]

SCV000800803Counsylcriteria provided, single submitter
Likely pathogenic
(Jan 31, 2018)
unknownclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV001372575Invitaecriteria provided, single submitter
Pathogenic
(Oct 16, 2019)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
East Asiangermlineunknown1not providednot providednot providednot providedreference population

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.

Lerner-Ellis JP, Anastasio N, Liu J, Coelho D, Suormala T, Stucki M, Loewy AD, Gurd S, Grundberg E, Morel CF, Watkins D, Baumgartner MR, Pastinen T, Rosenblatt DS, Fowler B.

Hum Mutat. 2009 Jul;30(7):1072-81. doi: 10.1002/humu.21001.

PubMed [citation]
PMID:
19370762
See all PubMed Citations (10)

Details of each submission

From Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center, SCV000267397.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1East Asian1not providednot providedreference population PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From Counsyl, SCV000800803.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001372575.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces arginine with tryptophan at codon 206 of the MMACHC protein (p.Arg206Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with methylmalonic aciduria and homocystinuria (PMID: 16311595, 20610126, 20631720, 26149271). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203832). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg206 amino acid residue in MMACHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30157807). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: May 10, 2021

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