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NM_002755.4(MAP2K1):c.608A>G (p.Glu203Gly) AND RASopathy

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 18, 2020
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV001250390.9

Allele description [Variation Report for NM_002755.4(MAP2K1):c.608A>G (p.Glu203Gly)]

NM_002755.4(MAP2K1):c.608A>G (p.Glu203Gly)

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.608A>G (p.Glu203Gly)
HGVS:
  • NC_000015.10:g.66481794A>G
  • NG_008305.1:g.99922A>G
  • NM_002755.4:c.608A>GMANE SELECT
  • NP_002746.1:p.Glu203Gly
  • LRG_725t1:c.608A>G
  • LRG_725:g.99922A>G
  • NC_000015.9:g.66774132A>G
  • NM_002755.3(MAP2K1):c.608A>G
  • NM_002755.3:c.608A>G
Links:
dbSNP: rs727503996
NCBI 1000 Genomes Browser:
rs727503996
Molecular consequence:
  • NM_002755.4:c.608A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
RASopathy
Synonyms:
rasopathies; Noonan spectrum disorder
Identifiers:
MONDO: MONDO:0021060; MedGen: C5555857

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001424752ClinGen RASopathy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)		Pathogenic
(May 18, 2020) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV001424752.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.608A>G (p.Glu203Gly) variant in MAP2K1 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV000965973.1,SCV000202961.7, GeneDx internal data). The variant arose de novo in two of the probands without confirmed parentage (PM6_Strong; SCV000965973.1, SCV000202961.7). Computational prediction tools and conservation analysis suggest that the c.608A>G (p.Glu203Gly) variant may impact protein function (PP3). Finally, the variant is located in MAP2K1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Moderate, PM2, PP3, PP2.

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

Last Updated: Oct 20, 2024