ClinVar Miner

Submissions for variant NM_004985.5(KRAS):c.108A>G (p.Ile36Met) (rs727503109)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844636 SCV000198471 likely pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2018-02-15 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000260877 SCV000329772 likely pathogenic not provided 2016-07-27 criteria provided, single submitter clinical testing The I36M variant has been reported previously as apparently de novo and in individuals diagnosed with Noonan syndrome (Lo et al., 2009; Zenker et al., 2007; Lee et al., 2011). The I36M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I36M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.
Integrated Genetics/Laboratory Corporation of America RCV000150891 SCV000919564 likely pathogenic Rasopathy 2018-10-25 criteria provided, single submitter clinical testing Variant summary: KRAS c.108A>G (p.Ile36Met) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 237482 control chromosomes (gnomAD). c.108A>G has been reported in the literature in individuals affected with Noonan Syndrome (Zenker 2007, Lo 2009, Lee 2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported; though an in vitro study demonstrated that substitutions of Ile36 caused severe impairment in Ras protein function, indicating the importance of this amino acid residue (Chung 1993). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic (1x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Blueprint Genetics RCV000260877 SCV000927544 likely pathogenic not provided 2018-02-23 criteria provided, single submitter clinical testing
Invitae RCV000150891 SCV000939441 likely pathogenic Rasopathy 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 36 of the KRAS protein (p.Ile36Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo and otherwise in individuals with clinical features of RASopathies spectrum (PMID: 18958496, 17056636). ClinVar contains an entry for this variant (Variation ID: 163768). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Institute for Genomic Statistics and Bioinformatics,University Hospital Bonn RCV000856729 SCV000999274 pathogenic Cardiofaciocutaneous syndrome 1 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000260877 SCV000809220 pathogenic not provided 2018-09-16 no assertion criteria provided research

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