Submissions for variant NM_001085049.3(MRAS):c.488A>G (p.Asn163Ser)

gnomAD frequency: 0.00013  dbSNP: rs536326964

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797929	SCV002041737	benign	not specified	2021-11-22	criteria provided, single submitter	clinical testing	Variant summary: MRAS c.488A>G (p.Asn163Ser) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) 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 9.1e-05 in 251458 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 60 fold of the estimated maximal expected allele frequency for a pathogenic variant in MRAS causing Noonan Syndrome phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.488A>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002034662	SCV002165065	uncertain significance	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 163 of the MRAS protein (p.Asn163Ser). This variant is present in population databases (rs536326964, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1329038). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.