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]

Link to SEPIO compliant JSON-LD document

Variant: NM_030662.3(MAP2K2):c.400T>C (p.Tyr134His)

CA119417

8274 (ClinVar)

Gene: MAP2K2

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b513b1fc-147c-4877-bb0a-38f55e252576

HGVS expressions

NM_030662.3:c.400T>C

NM_030662.3(MAP2K2):c.400T>C (p.Tyr134His)

NC_000019.10:g.4110559A>G

CM000681.2:g.4110559A>G

NC_000019.9:g.4110557A>G

CM000681.1:g.4110557A>G

NC_000019.8:g.4061557A>G

NG_007996.1:g.18570T>C

NM_030662.4:c.400T>C

ENST00000262948.9:c.400T>C

ENST00000394867.8:c.109T>C

ENST00000599345.1:n.597T>C

Likely Pathogenic

PP3 PP2 PM1 PM2 PS4_Moderate

PM5

Evidence Links 2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.400T>C (p.Tyr134His) variant in MAP2K2 was absent from large population studies (PM2). It has been identified in 3 patients with Cardiofaciocutaneous syndrome and 1 with Noonan syndrome (PS4_Moderate; SCV000063166.5, Hopital Universitaire Robert Debre internal data, PMIDs: 18042262, 27763634) Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; PMID 29493581). Moreover, a different pathogenic missense variant (p.Tyr134Cys) has been previously identified at this codon of MAP2K2 which may indicate that this residue is critical to the function of the protein (PM5 not met; ClinVar 177868). 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 missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Tyr134His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4_Moderate, PM1, PP2, PP3.

PP3

REVEL: 0.917

PP2

The variant is in MAP2K2, 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; PMID 29493581).

PM1

Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of MAP2K2 (PM1; PMID 29493581). PubMed:29493581

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4_Moderate

GeneDx: identified as a de novo variant by ABI in a fetus with Cystic hygroma noted on ultrasound. 46,XX karyotype reported by an outside laboratory. Advanced maternal age. Identified in an infant with cardiomyopathy, pulmonary stenosis, hepatosplenomegaly. Not counted LMM: identified in 6 year old boy with CFC Hopital Universitaire Robert Debre internal data: Seen twice Case 1 : height (1,55m at 25 years old), typical craniofacial phenotype, atrial septal defect, prenatal abnormalities (polyhydramnios). Unknown inheritance. Case 2: no clinical data. unknown inheritance. Classified as Pathogenic

The c.400T>C (p.Tyr134His) variant in MAP2K2 has been identified in 1 patient with clinical features of a RASopathy (PMID 18042262). PubMed:18042262

PM5

A different pathogenic missense variant has been previously identified at this codon of MAP2K2 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 177868). Cannot be applied in conjunction with PM1

Approved on: 2020-05-28

Published on: 2020-05-28

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