ClinVar Miner

Submissions for variant NM_004985.5(KRAS):c.173C>T (p.Thr58Ile) (rs104894364)

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Total submissions: 5
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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,Partners HealthCare 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one infant, and one child with clinical features of Noonan syndrome (Schubbert 2006, Houweling 2010, Croonen 2013, LMM-unpublished data).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 2017-07-13 criteria provided, single submitter clinical testing Heterozygous for the T58I mutation in the KRAS gene, consistent with the diagnosis of a disorder in the Noonan syndrome spectrum.Heterozygous for the T58I mutation in the KRAS gene, consistent with the diagnosis of a disorder in the Noonan syndrome spectrum.p.Thr58Ile (ACA>ATA): c.173 C>T in exon 3 of the KRAS gene (NM_004985.3)The T58I missense mutation in the KRAS gene has been reported previously in association with Noonan Syndrome (Schubbert et al., 2006), and a mutation in a neighboring residue, G60R, has been reported in associated with Cardio-Facio-Cutaneous (CFC) syndrome (Niihori et al., 2006). Therefore, the identification of the T58I mutation is consistent with a diagnosis of an autosomal dominant disorder of the Noonan-CFC-Costello syndrome spectrum. The variant is found in NOONAN panel(s).
Invitae RCV000704828 SCV000833798 pathogenic Rasopathy 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 58 of the KRAS protein (p.Thr58Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Noonan syndrome and Costello syndrome (PMID: 17704260, 20186801, 19396835) and has also been observed to be de novo in an individual affected with Noonan syndrome (PMID: 16474405). ClinVar contains an entry for this variant (Variation ID: 12588). Experimental studies have shown that this missense change impairs KRAS protein function (PMID: 16474405, 20949621 ). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013419 SCV000033666 pathogenic Noonan syndrome 3 2009-05-01 no assertion criteria provided literature only

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