Evidence Repository - Clinical Genome Resources

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_002755.4(MAP2K1):c.158T>C (p.Phe53Ser)

Curation Version - 3.3
Curation History
JSON LD for Version 3.3

CA279966

13350 (ClinVar)

Gene: MAP2K1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b78d797f-9630-4e8f-a1e3-8bf3ece401f5

Approved on: 2024-09-17

Published on: 2024-10-01

HGVS expressions

NM_002755.4:c.158T>C

NM_002755.4(MAP2K1):c.158T>C (p.Phe53Ser)

NC_000015.10:g.66435104T>C

CM000677.2:g.66435104T>C

NC_000015.9:g.66727442T>C

CM000677.1:g.66727442T>C

NC_000015.8:g.64514496T>C

NG_008305.1:g.53232T>C

ENST00000684779.1:c.92T>C

ENST00000685172.1:c.158T>C

ENST00000685763.1:c.158T>C

ENST00000686347.1:c.158T>C

ENST00000687191.1:n.594T>C

ENST00000689951.1:c.158T>C

ENST00000691077.1:c.158T>C

ENST00000691576.1:c.158T>C

ENST00000691937.1:c.158T>C

ENST00000692487.1:c.158T>C

ENST00000692683.1:c.92T>C

ENST00000693150.1:c.92T>C

ENST00000307102.10:c.158T>C

ENST00000307102.9:c.158T>C

ENST00000425818.2:n.669T>C

NM_002755.3:c.158T>C

Likely Pathogenic

PS3_Moderate PM1 PM2_Supporting PM6_Supporting PS4_Moderate PP2 PP3

BA1 BS1 BP4

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.158T>C variant in the MAP2K1 gene is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 53 (p.Phe53Ser). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.938 (PP3). The variant is located in the MAP2K1 gene, 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). Furthermore, the variant is in a location, analogous to MEK2 F57 residue, that has been defined by the ClinGen RASopathy Expert Panel functional domain of MAP2K1 (PM1). This variant has been reported in the literature in 4 individuals with clinical features of RASopathy with 1 unconfirmed de novo occurrence (PS4_Moderate, PM6_Supporting; PMIDs: 16439621, 18039235, 21062266, 30141192). ERK/MAPK phosphorylation assays showed that this variant led to significantly increased phosphorylation compared to wildtype (PS3_Moderate; PMID: 16439621, 17981815). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS3_Moderate, PS4_Moderate, PM1, PM2_Supporting, PM6_Supporting, PP2, PP3 (Specification Version 2.1, 9/17/2024)

PS3_Moderate

ERK/MAPK phosphorylation assays showed that this variant led to significantly increased phosphorylation compared to wildtype (PS3_Moderate; PMID: 16439621, 17981815)

PM1

The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of MAP2K1 (AA 43-61, PM1).

PM2_Supporting

This variant is absent from gnomAD v4.1.0

PM6_Supporting

The p.Phe53Ser variant in MAP2K1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6_Supporting; PMID 16439621).

PS4_Moderate

This variant has been reported in the literature in 4 individuals with clinical features of RASopathy with 1 unconfirmed de novo occurrence (PS4_Moderate, PMIDs: 16439621, 18039235, 21062266, 30141192)

PP2

The variant is in MAP2K1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2).

PP3

The computational predictor REVEL gives a score of 0.938 (PP3).

BA1

This variant is absent from gnomAD v4.1.0

BS1

This variant is absent from gnomAD v4.1.0

BP4

Computational prediction tools and conservation analysis suggest that the p.Phe53Ser variant may impact the protein (PP3).

Curation History

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