NM_002755.4(MAP2K1):c.848C>T (p.Ala283Val) AND Rasopathy

Clinical significance:Benign (Last evaluated: May 9, 2017)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_002755.4(MAP2K1):c.848C>T (p.Ala283Val)]

NM_002755.4(MAP2K1):c.848C>T (p.Ala283Val)

MAP2K1:mitogen-activated protein kinase kinase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_002755.4(MAP2K1):c.848C>T (p.Ala283Val)
Other names:
p.A283V:GCG>GTG; NM_002755.3(MAP2K1):c.848C>T
  • NC_000015.10:g.66485144C>T
  • NG_008305.1:g.103272C>T
  • NM_002755.3:c.848C>T
  • NM_002755.4:c.848C>TMANE SELECT
  • NP_002746.1:p.Ala283Val
  • NP_002746.1:p.Ala283Val
  • LRG_725t1:c.848C>T
  • LRG_725:g.103272C>T
  • LRG_725p1:p.Ala283Val
  • NC_000015.9:g.66777482C>T
  • c.848C>T
Protein change:
dbSNP: rs144080051
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_002755.3:c.848C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002755.4:c.848C>T - missense variant - [Sequence Ontology: SO:0001583]


rasopathies; Noonan spectrum disorder
MONDO: MONDO:0021060; MedGen: CN166718

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000616535ClinGen RASopathy Variant Curation Expert Panelreviewed by expert panel
(May 9, 2017)

Citation Link,

SCV001412748Invitaecriteria provided, single submitter
Uncertain significance
(Jul 4, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation



Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.

Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE.

Genome Med. 2017 Feb 6;9(1):13. doi: 10.1186/s13073-017-0403-7.

PubMed [citation]

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616535.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided


The filtering allele frequency of the c.848C>T (p.Ala283Val) variant in the MAP2K1 gene is 0.052% for African chromosomes by the Exome Aggregation Consortium (10/10366 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; Partners LMM, GeneDx internal data; GTR ID: 21766, 26957; ClinVar SCV000207935.12; SCV000061262.5). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5.

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

From Invitae, SCV001412748.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)


This sequence change replaces alanine with valine at codon 283 of the MAP2K1 protein (p.Ala283Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs144080051, ExAC 0.1%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MAP2K1-related disease. ClinVar contains an entry for this variant (Variation ID: 40756). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Aug 27, 2021

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