ClinVar Miner

Submissions for variant NM_006270.5(RRAS):c.409G>A (p.Val137Ile)

gnomAD frequency: 0.00006  dbSNP: rs757080959
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000632776 SCV000753962 uncertain significance Noonan syndrome 2022-03-09 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 527789). This variant has not been reported in the literature in individuals affected with RRAS-related conditions. This variant is present in population databases (rs757080959, gnomAD 0.005%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 137 of the RRAS protein (p.Val137Ile).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174918 SCV001338354 uncertain significance not specified 2020-02-13 criteria provided, single submitter clinical testing Variant summary: RRAS c.409G>A (p.Val137Ile) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251258 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.409G>A in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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