Submissions for variant NM_030662.4(MAP2K2):c.806C>G (p.Pro269Arg)

dbSNP: rs368064728

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV001172272	SCV001335311	uncertain significance	RASopathy	2020-03-09	reviewed by expert panel	curation	The c.806C>G (p.Pro269Arg) variant in MAP2K2 is absent from gnomAD (PM2). This variant has been observed in an individual with an alternate mechanism of disease (VCV000013329.8; Laboratory for Molecular Medicine internal data; BP5). Four apparently unaffected parental samples involved in whole exome testing were observed with this variant supporting that this variant is likely benign; however, this evidence does not meet current scoring criteria for BS2 at this time. Computational prediction tools and conservation analysis suggest that the p.Pro269Arg variant may impact the protein (PP3). In summary, the clinical significance of the p.Pro269Arg variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP3, PM2, BP5.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154524	SCV000204196	uncertain significance	not specified	2018-02-15	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000681198	SCV000808657	likely benign	not provided	2021-04-02	criteria provided, single submitter	clinical testing
Invitae	RCV001172272	SCV002286382	uncertain significance	RASopathy	2021-09-15	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MAP2K2 protein function. ClinVar contains an entry for this variant (Variation ID: 177876). This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. This variant is present in population databases (rs368064728, ExAC 0.002%). This sequence change replaces proline with arginine at codon 269 of the MAP2K2 protein (p.Pro269Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine.
Ambry Genetics	RCV003162628	SCV003869424	uncertain significance	Cardiovascular phenotype	2022-12-09	criteria provided, single submitter	clinical testing	The p.P269R variant (also known as c.806C>G), located in coding exon 7 of the MAP2K2 gene, results from a C to G substitution at nucleotide position 806. The proline at codon 269 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003416007	SCV004106632	uncertain significance	MAP2K2-related condition	2023-04-28	criteria provided, single submitter	clinical testing	The MAP2K2 c.806C>G variant is predicted to result in the amino acid substitution p.Pro269Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.00095% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-4099312-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.