Submissions for variant NM_002755.4(MAP2K1):c.516+1G>A

dbSNP: rs1240248728

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001361783	SCV001557773	uncertain significance	RASopathy	2024-07-03	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the MAP2K1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MAP2K1 cause disease. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MAP2K1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1053438). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001586147	SCV001811891	uncertain significance	not provided	2019-07-30	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Canonical splice site variant which may result in abnormal gene splicing; however, MAP2K1-related disorders are caused by a gain of function variants and loss of function is not a known mechanism of disease
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002254723	SCV002525973	uncertain significance	Cardiofaciocutaneous syndrome 3	2022-01-14	criteria provided, single submitter	clinical testing	The MAP2K1 c.516+1G>A intronic change results from a G to A substitution at the +1 position of intron 4 of the MAP2K1 gene. The disease mechanism for CFC is gain-of-function caused by heterozygous missense changes, whereas protein-truncating and splice variants do not have an established correlation to disease (PMID: 16439621). This variant is predicted to result in loss of the native splice donor site (PP3) and RNA data demonstrates skipping of exon 4 in at least 37% of mutant reads resulting in in-frame splicing between exon 3 and exon 5 (PM4_supporitng; internal data). This variant is absent in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). To our knowledge, this variant has not been reported in the literature in individuals with MAP2K1-related disease. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): PM2_supporitng, PM4_supporting, PP3.