NM_002755.4(MAP2K1):c.383G>T (p.Gly128Val) AND not provided

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Nov 27, 2017)

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:
RCV000207493.2

Allele description [Variation Report for NM_002755.4(MAP2K1):c.383G>T (p.Gly128Val)]

NM_002755.4(MAP2K1):c.383G>T (p.Gly128Val)

Gene:
MAP2K1:mitogen-activated protein kinase kinase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q22.31
Genomic location:
Preferred name:
NM_002755.4(MAP2K1):c.383G>T (p.Gly128Val)
HGVS:
  • NC_000015.10:g.66436837G>T
  • NG_008305.1:g.54965G>T
  • NM_002755.3:c.383G>T
  • NM_002755.4:c.383G>TMANE SELECT
  • NP_002746.1:p.Gly128Val
  • NP_002746.1:p.Gly128Val
  • LRG_725t1:c.383G>T
  • LRG_725:g.54965G>T
  • LRG_725p1:p.Gly128Val
  • NC_000015.9:g.66729175G>T
  • Q02750:p.Gly128Val
  • c.383G>T
Protein change:
G128V; GLY128VAL
Links:
UniProtKB: Q02750#VAR_069780; OMIM: 176872.0003; dbSNP: rs121908596
NCBI 1000 Genomes Browser:
rs121908596
Molecular consequence:
  • NM_002755.3:c.383G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002755.4:c.383G>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000263047Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Childrencriteria provided, single submitter
Likely pathogenic
(Jul 21, 2015)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000808249GeneDxcriteria provided, single submitter
Pathogenic
(Nov 27, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome.

Schulz AL, Albrecht B, Arici C, van der Burgt I, Buske A, Gillessen-Kaesbach G, Heller R, Horn D, Hübner CA, Korenke GC, König R, Kress W, Krüger G, Meinecke P, Mücke J, Plecko B, Rossier E, Schinzel A, Schulze A, Seemanova E, Seidel H, Spranger S, et al.

Clin Genet. 2008 Jan;73(1):62-70. Epub 2007 Nov 27.

PubMed [citation]
PMID:
18042262

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

Details of each submission

From Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children, SCV000263047.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided1not providednot providednot provided

From GeneDx, SCV000808249.1

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

Description

The G128V missense variant in the MAP2K1 gene has been reported previously as de novo and in association with cardiofaciocutaneous syndrome (Schulz et al., 2008). The G128V variant is not observed in large population cohorts (Lek et al., 2016). The G128V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Yet, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Transgenic studies in zebrafish have shown increased pMEK levels and abnormal phenotypic features (Jinal et al., 2017). Missense variants in nearby residues (P124Q/L, Y130H/N/C) have been reported in the Human Gene Mutation Database in association with RASopathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret this variant as pathogenic.

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

Last Updated: Sep 29, 2021

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