ClinVar Miner

Submissions for variant NM_033360.4(KRAS):c.194G>T (p.Ser65Ile) (rs1555194026)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000680027 SCV001424735 likely pathogenic Rasopathy 2020-05-18 reviewed by expert panel curation The c.194G>T (p.Ser65Ile) variant in KRAS was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 2 probands with clinical features of a RASopathy (PS4_Supporting; SCV000599968.1, PMID: 26822237, 25326635, Invitae internal data). The variant arose de novo in one of the probands with confirmed parentage (PS2; SCV000599968.1, PMID:26822237, 25326635). The variant is located in KRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581):, PS2, PS4_Supporting, PM2, PP2.
Baylor Genetics RCV000680027 SCV000807466 uncertain significance Rasopathy 2017-09-01 criteria provided, single submitter clinical testing Likely pathogenicity based on finding it once in our laboratory de novo in an 8-year-old female with global delays, hypotonia, failure to thrive, short stature, thin corpus callosum, epilepsy, small optic nerve, ptosis, coarse facies, joint contractures, hypothyroidism
Invitae RCV000680027 SCV001406346 uncertain significance Rasopathy 2019-07-23 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 65 of the KRAS protein (p.Ser65Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with clinical features of KRAS-related conditions (PMID: 26822237). ClinVar contains an entry for this variant (Variation ID: 438796). 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. 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.
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000505640 SCV000599968 likely pathogenic Noonan syndrome 3 2014-08-25 no assertion criteria provided research Likely pathogenicity based on finding it once in this study de novo in a 8-year-old female with plexiform neurofibroma, hypertelorism, ptosis, pulmonic stenosis, scoliosis, skeletal anomalies, developmental delay

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