Variant: NM_030662.4(MAP2K2):c.170T>G (p.Phe57Cys)

CA279958

8272 (ClinVar)

Gene: MAP2K2

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 07aecf91-9cf2-48c7-b101-b21e809f57a4

Approved on: 2024-12-03

Published on: 2025-03-31

HGVS expressions

NM_030662.4:c.170T>G
NM_030662.4(MAP2K2):c.170T>G (p.Phe57Cys)
NC_000019.10:g.4117552A>C
CM000681.2:g.4117552A>C
NC_000019.9:g.4117550A>C
CM000681.1:g.4117550A>C
NC_000019.8:g.4068550A>C
NG_007996.1:g.11577T>G
ENST00000394867.9:n.609T>G
ENST00000687128.1:n.609T>G
ENST00000262948.10:c.170T>G
ENST00000262948.9:c.170T>G
ENST00000394867.8:c.-122T>G
ENST00000599345.1:n.367T>G
NM_030662.3:c.170T>G

Pathogenic

• Met criteria codes: PM2_Supporting PP3 PM6 PS3_Supporting PM1 PM5 PS4_Moderate

• Not Met criteria codes: BS1 BS3 BP4 BA1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 2.3.0

Evidence submitted by expert panel

RASopathy VCEP

The c.170T>G variant in the MAP2K2 gene is a missense variant predicted to cause substitution of phenylalanine by cysteine at amino acid 57 (p.Phe57Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.959, predicting a damaging impact on protein function (PP3). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of MAP2K2 (PM1, AA 47-65). Furthermore, other pathogenic missense variants has been previously identified at this codon of MAP2K2 (Phe57Val, Phe57Ile, Phe57Leu) and in nearby residues in association with CFC syndrome, which may indicate that this residue is critical to the function of the protein (PM5). This variant has been identified in at least 4 patients with RASopathy, of which 1 was an unconfirmed de novo occurrence (PS4_Moderate, PM6; GenomeConnect, ClinVar: SCV002047662.1; PMID: 16439621, 18039235, 21062266). ERK phosphorylation assays showed that this variant led to increased phosphorylation compared to wild-type (PS3_Supporting; PMID: 16439621, 17981815). 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: PS4_Moderate, PM1, PM5, PM6, PS3_Supporting, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024)

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1
• PP3: The computational predictor REVEL gives a score of 0.959, predicting a damaging impact on protein function
• PM6: The p.Phe57Cys variant in MAP2K2 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PMID 16439621).
• PS3_Supporting: ERK phosphorylation assays showed that this variant led to increased phosphorylation compared to wild-type (PMID: 16439621, 17981815)
• PM1: This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of MAP2K2 (aa 47-65)
• PM5: other pathogenic missense variants has been previously identified in association with CFC syndrome at this codon of MAP2K2 (Phe57Val, Phe57Ile, Phe57Leu) and in nearby residues, which may indicate that this residue is critical to the function of the protein
• PS4_Moderate: This variant has been identified in at least 4 patients with RASopathy (GenomeConnect, ClinVar: SCV002047662.1; PMID: 16439621, 18039235, 21062266)

Not Met criteria codes

• BS1: This variant is absent from gnomAD v2.1.1
• BS3: In vitro functional studies provide some evidence that the p.Phe57Cys variant may impact protein function
• BP4: The computational predictor REVEL gives a score of 0.959, predicting a damaging impact on protein function
• BA1: This variant is absent from gnomAD v2.1.1