ClinVar Miner

Submissions for variant NM_004985.5(KRAS):c.178G>A (p.Gly60Ser) (rs104894359)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000157934 SCV000207869 pathogenic not provided 2018-06-18 criteria provided, single submitter clinical testing The G60S variant in the KRAS gene has been reported previously in an individual with Noonan syndrome and craniosynostosis (Kratz et al., 2009). The G60S variant is not observed in large population databases (Lek et al., 2016). The G60S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the nucleotide binding region. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. We interpret G60S as a pathogenic variant.
Invitae RCV000689097 SCV000816735 pathogenic Rasopathy 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 60 of the KRAS protein (p.Gly60Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with Noonan syndrome (PMID: 19396835). ClinVar contains an entry for this variant (Variation ID: 12597). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The p.Gly60 amino acid residue in KRAS has been determined to be clinically significant (PMID: 16474404, 28650561, 26242988, 20949621). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013428 SCV000033675 pathogenic Noonan syndrome 3 2009-05-01 no assertion criteria provided literature only

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