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

dbSNP: rs104894359

Total submissions: 9

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, Mass General Brigham 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	2022-07-15	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 12586). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 16474404, 26242988, 28650561). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 60 of the KRAS protein (p.Gly60Arg). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects KRAS function (PMID: 20949621).
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
3billion	RCV000013416	SCV003841912	pathogenic	Cardiofaciocutaneous syndrome 2	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20949621). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000012586 / PMID: 16474404) and different missense changes at the same codon (p.Gly60Ser, p.Gly60Val / ClinVar ID: VCV000012597, VCV000163766 / PMID: 19396835) Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV003313917	SCV004013932	pathogenic	Noonan syndrome 3	2023-06-13	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP3, PP5
OMIM	RCV000013416	SCV000033663	pathogenic	Cardiofaciocutaneous syndrome 2	2006-03-01	no assertion criteria provided	literature only