Submissions for variant NM_002755.4(MAP2K1):c.275T>G (p.Leu92Arg)

dbSNP: rs397516791

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV004760354	SCV000616534	pathogenic	RASopathy	2024-09-17	reviewed by expert panel	curation	The c.275T>G variant in the MAP2K1 gene is a missense variant predicted to cause substitution of leucine by arginine at amino acid 92 (p.Leu92Arg). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.793 (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). This variant has been reported in 4 independent patients with clinical feature of a RASopathy, 1 as a confirmed de novo occurrence and 2 as unconfirmed de novo occurrences (PS4_Moderate, PM6_VeryStrong; GeneDx, APHP-Robert Debré hospital, Laboratory for Molecular Medicine internal data; ClinVar SCV000207940.11, SCV000965969.1, SCV000061251.5, PMID: 35524774). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PM6_VeryStrong, PS4_Moderate, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 09/17/2024)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000522848	SCV000061251	likely pathogenic	Cardio-facio-cutaneous syndrome	2019-02-11	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000158005	SCV000207940	likely pathogenic	not provided	2017-01-13	criteria provided, single submitter	clinical testing	A novel L92R variant that is likely pathogenic was identified in the MAP2K1 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It has, however, been observed to be inherited in an apparently de novo manner in two patients tested at GeneDx. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. L92R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species; however, in in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813322	SCV002060796	uncertain significance	Noonan syndrome and Noonan-related syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000522848	SCV000965969	likely pathogenic	Cardio-facio-cutaneous syndrome		no assertion criteria provided	clinical testing