ClinVar Miner

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

dbSNP: rs727503109
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Mass General Brigham 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 2021-01-25 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 18958496, 17056636, 18470943, 21784453, 24803665, 25525159)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 pathogenic RASopathy 2021-08-13 criteria provided, single submitter clinical testing
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
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000260877 SCV001808517 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000260877 SCV001952076 pathogenic not provided no assertion criteria provided clinical testing

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