Submissions for variant NM_002890.3(RASA1):c.2725A>G (p.Ile909Val)

gnomAD frequency: 0.00011  dbSNP: rs113316011

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756590	SCV000884447	uncertain significance	not provided	2017-10-13	criteria provided, single submitter	clinical testing	The p.Ile909Val variant (rs113316011) has not been reported in the medical literature, is not listed in gene-specific variant databases, nor has it been previously identified in our laboratory. The p.Ile909Val variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.010% (identified in 28 out of 276,160 chromosomes). The isoleucine at codon 909 is highly conserved considering 11 species up to baker’s yeast (Alamut software v2.10.0), and computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: damaging, PolyPhen2: benign, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.Ile909Val variant cannot be determined with certainty.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035662	SCV001198996	uncertain significance	Capillary malformation-arteriovenous malformation syndrome	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 909 of the RASA1 protein (p.Ile909Val). This variant is present in population databases (rs113316011, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RASA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 618342). 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.
Ambry Genetics	RCV002458354	SCV002738676	uncertain significance	Cardiovascular phenotype	2021-07-27	criteria provided, single submitter	clinical testing	The p.I909V variant (also known as c.2725A>G), located in coding exon 21 of the RASA1 gene, results from an A to G substitution at nucleotide position 2725. The isoleucine at codon 909 is replaced by valine, an amino acid with highly similar 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.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV000756590	SCV005326335	uncertain significance	not provided		criteria provided, single submitter	clinical testing	The p.Ile909Val variant substitutes the isoleucine at amino acid position 909 with a valine. This variant occurs in the Ras-GAP domain (Uniprot: 20936) of the RASA1 protein. This variant is present at a low frequency in large population studies (120 of 1,611,784 alleles, gnomAD v4.0.0). In silico predictions trend towards damaging but are inconclusive. This variant is absent from the medical literature, but has been reported in few individuals in patient databases (ClinVar, Franklin).