ClinVar Miner

Submissions for variant NM_006270.5(RRAS):c.627G>T (p.Lys209Asn)

gnomAD frequency: 0.00002  dbSNP: rs771557284
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001052997 SCV001217238 uncertain significance Noonan syndrome 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 209 of the RRAS protein (p.Lys209Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs771557284, ExAC 0.02%). This variant has not been reported in the literature in individuals with RRAS-related conditions. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193594 SCV001362524 uncertain significance not specified 2019-11-18 criteria provided, single submitter clinical testing Variant summary: RRAS c.627G>T (p.Lys209Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 152962 control chromosomes. 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.627G>T in individuals affected with Noonan Syndrome and Related Conditions 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 uncertain significance.

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