ClinVar Miner

Submissions for variant NM_004985.5(KRAS):c.178G>C (p.Gly60Arg) (rs104894359)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000521390 SCV000616370 pathogenic Cardio-facio-cutaneous syndrome 2017-04-03 reviewed by expert panel curation The c.178G>C (p.Gly60Arg) variant in KRAS has been reported in the literature as a de novo occurrence in 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 16474404, 20949621). In vitro functional studies provide some evidence that the p.Gly60Arg variant may impact protein function (PS3; PMID 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in KRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of KRAS (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly60Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PS3, PM2, PM1, PP3, PP2.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844635 SCV000203923 pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2015-09-29 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000254661 SCV000207870 pathogenic not provided 2016-04-20 criteria provided, single submitter clinical testing The G60R missense variant in the KRAS gene has been reported previously in association with cardio-facio-cutaneous (CFC) syndrome and observed de novo (Niihori et al., 2006; Joyce et al., 2015). The G60R 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. G60R 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 highly conserved position within the GTP binding region. Functional in vitro studies have demonstrated that G60R results in an increase in kinase activity (MEK, ERK, and AKT) (Gremer et al., 2011). Therefore, the presence of this variant is consistent with a diagnosis of cardio-facio-cutaneous syndrome.
Invitae RCV000157935 SCV000813167 pathogenic Rasopathy 2018-06-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 60 of the KRAS protein (p.Gly60Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with cardio-facio-cutaneous syndrome, including several in which the variant was found to be de novo (PMID: 16474404, 28650561, 26242988). ClinVar contains an entry for this variant (Variation ID: 12586). Experimental studies have shown that this missense change significantly impairs KRAS GAP sensitivity and effector binding (PMID: 20949621). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000254661 SCV000927431 pathogenic not provided 2017-10-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV001267316 SCV001445497 pathogenic Inborn genetic diseases 2016-02-19 criteria provided, single submitter clinical testing
OMIM RCV000013416 SCV000033663 pathogenic Cardiofaciocutaneous syndrome 2 2006-03-01 no assertion criteria provided literature only

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