Submissions for variant NM_004985.5(KRAS):c.173C>T (p.Thr58Ile)

dbSNP: rs104894364

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000211785	SCV000616369	pathogenic	Noonan syndrome	2017-04-03	reviewed by expert panel	curation	The c.173C>T (p.Thr58Ile) variant in KRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6_Strong; PMID 23321623, 20112233, 16921267, 16474405, 22488832, 18247425, 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In vitro functional studies provide some evidence that the p.Thr58Ile variant may impact protein function (PS3; PMID: 23321623, 20949621, 16921267). 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). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr58Ile variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS3, PM2, PM1, PP2, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211785	SCV000198470	pathogenic	Noonan syndrome	2014-03-25	criteria provided, single submitter	clinical testing	The Thr58Ile variant in KRAS has been previously reported in at least one fetus, one infant, and one child with clinical features of Noonan syndrome (Schubbert 2006, Houweling 2010, Croonen 2013, LMM-unpublished data). In both the fetus and the infant, the variant was reported to be de novo (Schubbert 2006, Croonen 201 3). Functional studies show that this variant impacts the protein's GTPase activ ity and leads to overall enhanced downstream signaling (Schubbert 2006, Gremer 2 010). In addition, this variant was absent from large population studies. In sum mary, this variant meets our criteria to be classified as pathogenic (http://pcp gm.partners.org/LMM).
GeneDx	RCV000157933	SCV000207868	pathogenic	not provided	2024-04-12	criteria provided, single submitter	clinical testing	Identified in patients with Noonan syndrome and Noonan-like features referred for genetic testing at GeneDx and in published literature, including as a de novo variant without confirmed parentage (PMID: 16474405, 23321623); Published functional studies demonstrate a damaging effect caused by defective GTP hydrolysis and hypersensitive responsiveness to GTPase activating proteins resulting in an overall enhancement in RAS signaling (PMID: 16474405, 20949621); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19396835, 16921267, 20949621, 23321623, 30055033, 26918529, 32021610, 34539730, 33726816, 35418823, 34643321, 16474405, 17875937, 29493581)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704828	SCV000833798	pathogenic	RASopathy	2024-09-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 58 of the KRAS protein (p.Thr58Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome and Costello syndrome and Noonan syndrome (PMID: 16474405, 17704260, 19396835, 20186801). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12588). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt KRAS function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KRAS function (PMID: 16474405, 20949621). For these reasons, this variant has been classified as Pathogenic.
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV000013419	SCV001739479	pathogenic	Noonan syndrome 3	2020-02-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV000013419	SCV002499692	pathogenic	Noonan syndrome 3	2022-04-14	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM1,PM2,PM6,PP3,PP5
OMIM	RCV000013419	SCV000033666	pathogenic	Noonan syndrome 3	2009-05-01	no assertion criteria provided	literature only