Submissions for variant NM_033360.4(KRAS):c.178G>A (p.Gly60Ser)

dbSNP: rs104894359

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157934	SCV000207869	pathogenic	not provided	2022-11-25	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 28639239, 19396835, 30732632, 31219622, 35441720)
Invitae	RCV000689097	SCV000816735	pathogenic	RASopathy	2022-07-12	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly60 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16474404, 26242988, 28650561). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 12597). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 19396835, 30732632). 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 serine, which is neutral and polar, at codon 60 of the KRAS protein (p.Gly60Ser).
DASA	RCV000013428	SCV002318974	pathogenic	Noonan syndrome 3	2022-03-25	criteria provided, single submitter	clinical testing	The c.178G>A;p.(Gly60Ser) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12597; PMID: 19396835) -PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (RAS) - PM1. This variant is not present in population databases (rs104894359- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 12586) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 19396835) - PM6. Missense variant in KRAS that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470709	SCV002768383	pathogenic	Cardiofaciocutaneous syndrome 2	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant, NM_004985.4(KRAS):c.178G>A, has been identified in exon 3 of 5 of the KRAS gene. The variant is predicted to result in a minor amino acid change from glycine to serine at position 60 of the protein (NP_004976.2(KRAS):p.(Gly60Ser)). The glycine residue at this position has very high conservation (100 vertebrates, UCSC) and is known as a mutational hotspot for Noonan syndrom and related disorders that locates within the critical binding and interaction site of Ras domain (Gremer, L. et al. (2011)). In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD). The variant has been previously described as a known pathogenic variant in multiple patients with Noonan syndrome (ClinVar, Kratz, CP. et al. (2009), Leung, GKC. et al. (2018), Chen, H. et al. (2019)). Multiple variants in the same codon resulting in various changes have also been reported as pathogenic (ClinVar, Zenker, M. et al. (2007), Nosan, G. et al. (2013), Chen, H. et al. (2019)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
OMIM	RCV000013428	SCV000033675	pathogenic	Noonan syndrome 3	2009-05-01	no assertion criteria provided	literature only
Prenatal Genetic Diagnosis Laboratory, The Chinese University of Hong Kong	RCV000013428	SCV002498739	pathogenic	Noonan syndrome 3	2021-07-05	no assertion criteria provided	clinical testing	This variant c.178G>A(p.G60S) was previously reported to be de novo in a patient with Noonan syndrome [PMID:19396835] (PS2). The p.Gly60 amino acid residue in KRAS has been determined to be clinically significant and confirmed by functional studies [PMID: 16474404, 20949621, 26242988, 28650561] (PM1). The variant is absent in the gnomAD database (PM2). Computational evidence support a deleterious effect on the gene product (PP3) .This variant has been classified as pathogenic by multiple labs in ClinVar [Variation ID: 12597] (PP5). This variant c.178G>A(p.G60S) is interpreted as pathogenic according to ACMG/AMP guidelines.