Variant: NM_030662.4(MAP2K2):c.383C>A (p.Pro128Gln)

CA279962

8275 (ClinVar)

Gene: MAP2K2

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 307f4b6c-ef49-48bd-98e2-5cf382642800

Approved on: 2024-09-17

Published on: 2024-10-02

HGVS expressions

NM_030662.4:c.383C>A
NM_030662.4(MAP2K2):c.383C>A (p.Pro128Gln)
NC_000019.10:g.4110576G>T
CM000681.2:g.4110576G>T
NC_000019.9:g.4110574G>T
CM000681.1:g.4110574G>T
NC_000019.8:g.4061574G>T
NG_007996.1:g.18553C>A
ENST00000394867.9:n.822C>A
ENST00000687128.1:n.822C>A
ENST00000262948.10:c.383C>A
ENST00000262948.9:c.383C>A
ENST00000394867.8:c.92C>A
ENST00000599345.1:n.580C>A
NM_030662.3:c.383C>A

Pathogenic

• Met criteria codes: PP3 PM1 PM2_Supporting PS4_Supporting PS3_Supporting PP1_Strong

• Not Met criteria codes: PM5 BA1 BS1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 2.1.0

Evidence submitted by expert panel

RASopathy VCEP

The c.383C>A variant in the MAP2K2 gene is a missense variant predicted to cause substitution of proline by glutamine at amino acid 128 (p.Pro128Gln). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.928 (PP3). This variant is located in a functional domain supporting pathogenicity (PM1). This variant has been reported to segregate with clinical features of a RASopathy in at least 7 family members of the proband (PS4_Supporting, PP1_Strong; 20358587). ERK phosphorylation assay showed that this variant led to increased ERK phosphorylation compared to wild-type (PS3_P; PMID 20358587). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PP1_Strong, PM1, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP3 (Specification Version 2.1, 09/17/2024)

Met criteria codes

• PP3: Computational prediction tools and conservation analysis suggest that the p.Pro124Gln variant may impact the protein (PP3).
• PM1: The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of MAP2K2 ( AA 128-138, PM1).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0
• PS4_Supporting: This variant was reported in 1 proband with a RASopathy (PS4_Supporting, PMID: 2035858)
• PS3_Supporting: In vitro functional studies showed that the p.Pro124Gln variant increased ERK phosphorylation compared to wild-type (PS3; PMID 20358587).
• PP1_Strong: The p.Pro124Gln variant in MAP2K2 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_S; PMID: 20358587).

Not Met criteria codes

• PM5: Not applied as there were not enough probands with the other variants. 2 other missense change observed in the residue, 1 pathogenic missense variant (p.Pro128Leu; ClinVar: 666272) and 1 VUS missense variant (p.Pro128Arg; ClinVar: 40792)
• BA1: This variant is absent from gnomAD v4.1.0
• BS1: This variant is absent from gnomAD v4.1.0