ClinVar Miner

Submissions for variant NM_006270.5(RRAS):c.64G>T (p.Gly22Trp)

gnomAD frequency: 0.00003  dbSNP: rs754976061
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000632777 SCV000753963 uncertain significance Noonan syndrome 2022-06-29 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 527790). This variant has not been reported in the literature in individuals affected with RRAS-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 22 of the RRAS protein (p.Gly22Trp).
CeGaT Center for Human Genetics Tuebingen RCV003411498 SCV004140443 uncertain significance not provided 2023-10-01 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000632777 SCV004171409 uncertain significance Noonan syndrome 2023-11-13 criteria provided, single submitter clinical testing The RRAS c.64G>T (p.Gly22Trp) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Noonan syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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