Submissions for variant NM_030662.4(MAP2K2):c.841C>T (p.Arg281Trp)

gnomAD frequency: 0.00004  dbSNP: rs759998177

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174923	SCV001338360	likely benign	not specified	2024-02-26	criteria provided, single submitter	clinical testing	Variant summary: MAP2K2 c.841C>T (p.Arg281Trp) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 1605404 control chromosomes (gnomAD database v4.0.0). The observed variant frequency is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Noonan Syndrome And Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.841C>T in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 917722). Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873656	SCV002110934	uncertain significance	RASopathy	2023-09-23	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 not expected to disrupt MAP2K2 protein function. ClinVar contains an entry for this variant (Variation ID: 917722). This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. This variant is present in population databases (rs759998177, gnomAD 0.008%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 281 of the MAP2K2 protein (p.Arg281Trp).
Ambry Genetics	RCV002445415	SCV002678352	uncertain significance	Cardiovascular phenotype	2022-08-24	criteria provided, single submitter	clinical testing	The p.R281W variant (also known as c.841C>T), located in coding exon 7 of the MAP2K2 gene, results from a C to T substitution at nucleotide position 841. The arginine at codon 281 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.