Evidence Repository - GenboreeKB

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_030662.3(MAP2K2):c.842G>A (p.Arg281Gln)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA403385475

569590 (ClinVar)

Gene: MAP2K2

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: dfec0bf2-cccf-4932-8cf2-6dabf182615f

Approved on: 2020-03-19

Published on: 2020-03-23

HGVS expressions

NM_030662.3:c.842G>A

NM_030662.3(MAP2K2):c.842G>A (p.Arg281Gln)

NC_000019.10:g.4099278C>T

CM000681.2:g.4099278C>T

NC_000019.9:g.4099276C>T

CM000681.1:g.4099276C>T

NC_000019.8:g.4050276C>T

NG_007996.1:g.29851G>A

ENST00000394867.9:n.1281G>A

ENST00000687128.1:n.1281G>A

ENST00000688002.1:n.1136G>A

ENST00000689792.1:n.746G>A

ENST00000262948.10:c.842G>A

ENST00000262948.9:c.842G>A

ENST00000394867.8:c.551G>A

ENST00000593364.5:n.789G>A

ENST00000595715.1:n.657G>A

ENST00000597263.5:n.169+1741G>A

ENST00000599021.1:c.29+1741G>A

ENST00000600584.5:n.1402G>A

ENST00000601786.5:n.1143G>A

NM_030662.4:c.842G>A

Uncertain Significance

PP2 BP4

PM2 PM1 PM5 BS2

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.842G>A (p.Arg281Gln) variant in MAP2K2 was present in 0.007324% (1/13654) of Latino chromosomes in gnomAD v3. It was observed in one healthy adult male who did not have features of a RASopathy (BS2 not met; Baylor internal data). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Computational analysis and splice site predictors suggest that this variant does not impact the protein (BP4). In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied: PP2, BP4.

PP2

MAP2K2 is a missense-constrained gene.

BP4

REVEL score 0.032. May add a 3' splice site (predicted by SpliceSiteFinder-like and MaxEntScan but not NNSPLICE or GeneSplicer), however impact to splicing is not predicted to align with the GOF mechanism for MAP2K2-associated RASopathy. 1 animal in the UCSC database (guinea pig) has Q at this site.

PM2

Present in 0.007324% (1/13654) of Latino chromosomes in gnomAD v3. Absent from gnomAD v2.1.1.

PM1

Does not occur between aa 47-65 or 128-138.

PM5

Only 1 other variant in this codon, c.841C>T (p.Arg281Trp), has been reported. It was absent from ClinVar and was classified as a VUS by the EP.

BS2

This variant was seen in 3 unaffected individuals (Invitae internal data, SCV000817942.1; Baylor internal data). One case was a juvenile male tested because his father had idiopathic HCM, but the proband was supposedly unaffected and healthy. This case was not counted because the indication for testing was HCM. In 2 other cases, the variant was inherited and the fathers of the probands were noted to be asymptomatic. One proband was suspected to have NS; the other did not have a diagnosis.

Curation History

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