NM_000255.4(MMUT):c.670G>T (p.Glu224Ter) AND not provided

Clinical significance:Pathogenic (Last evaluated: Mar 23, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000760390.2

Allele description [Variation Report for NM_000255.4(MMUT):c.670G>T (p.Glu224Ter)]

NM_000255.4(MMUT):c.670G>T (p.Glu224Ter)

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.670G>T (p.Glu224Ter)
HGVS:
  • NC_000006.12:g.49457774C>A
  • NG_007100.1:g.10366G>T
  • NM_000255.4:c.670G>TMANE SELECT
  • NP_000246.2:p.Glu224Ter
  • NC_000006.11:g.49425487C>A
  • NM_000255.3:c.670G>T
Protein change:
E224*
Links:
dbSNP: rs1554160638
NCBI 1000 Genomes Browser:
rs1554160638
Molecular consequence:
  • NM_000255.4:c.670G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000890261GeneDxcriteria provided, single submitter
Pathogenic
(Feb 1, 2019)
germlineclinical testing

Citation Link,

SCV001223502Invitaecriteria provided, single submitter
Pathogenic
(Mar 23, 2019)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype.

Worgan LC, Niles K, Tirone JC, Hofmann A, Verner A, Sammak A, Kucic T, Lepage P, Rosenblatt DS.

Hum Mutat. 2006 Jan;27(1):31-43.

PubMed [citation]
PMID:
16281286

Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants.

Martínez MA, Rincón A, Desviat LR, Merinero B, Ugarte M, Pérez B.

Mol Genet Metab. 2005 Apr;84(4):317-25. Epub 2005 Jan 22.

PubMed [citation]
PMID:
15781192
See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000890261.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The E224X variant has been reported previously in an individual with mut0 MMA who also had a second nonsense variant identified in the MUT gene (Worgan et al., 2006). The E224X variant is not observed in large population cohorts (Lek et al., 2016). This E224X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret E224X as pathogenic.

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

From Invitae, SCV001223502.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Glu224*) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with methylmalonic aciduria (PMID: 16281286). ClinVar contains an entry for this variant (Variation ID: 552718). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). 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: Nov 27, 2021

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