ClinVar Miner

Submissions for variant NM_004985.5(KRAS):c.101C>T (p.Pro34Leu) (rs104894366)

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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 RCV000150892 SCV000616368 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.101C>T (p.Pro34Leu) variant in KRAS has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2; PMID 17056636, 20949621). This variant was absent from large population studies (PM2; ExAC, A different pathogenic missense variant has been previously identified at this codon of KRAS which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 12590). Computational prediction tools and conservation analysis suggest that the p.Pro34Leu variant may impact the protein (PP3; PMID: 24803665). 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). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PS2, PM2, PM5, PP3, PP2.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150892 SCV000198472 pathogenic Noonan syndrome 2013-06-04 criteria provided, single submitter clinical testing The Pro34Leu variant in KRAS has not been identified by our laboratory, but has been reported in one individual with Noonan syndrome where it was demonstrated t o have occurred de novo (Zenker 2007). Another variant at the same nucleotide p osition (c.101C>A, p.Pro34Gln) has also been reported in another patient with No onan syndrome where it too, was demonstrated to have occurred de novo (Zenker 20 07). Functional studies have shown that the Pro34Leu variant results in a GTPas e-Activating Protein (GAP)-resistant conformation and consequently, to a weak ga in-of-function, consistent with disease pathogenesis (Gremer 2010). This variant has not been reported in large population studies, consistent with a pathogenic role. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may impact the protein. In summary, this variant meets our criteria to be classified as pathogenic bas ed on the de novo occurrence and supportive functional studies (http://pcpgm.par
GeneDx RCV000157668 SCV000207884 pathogenic not provided 2012-03-21 criteria provided, single submitter clinical testing The P34L missense mutation in the KRAS gene has been reported previously in association with Noonan syndrome (Zenker et al., 2007). Other missense mutations at the same codon (P34Q and P34R) have been reported in association with KRAS-related disorders (Zenker et al., 2007; Schubbert et al., 2006). Therefore, its presence is consistent with a diagnosis of a KRAS-related disorder. The variant is found in NOONAN panel(s).
Invitae RCV000232330 SCV000288784 pathogenic Rasopathy 2016-03-09 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 34 of the KRAS protein (p.Pro34Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (rs104894366, ExAC no frequency). This variant has been shown to arise de novo in individuals affected with Noonan syndrome (PMID: 17056636). ClinVar contains an entry for this variant (Variation ID: 40454). Two other missense substitution at this codon (p.Pro34Arg and p.Pro34Gln) have also been shown to arise de novo in individuals affected with KRAS-related disorders. The p.Pro34Gln substitution was reported in a patient affected with Noonan syndrome (PMID: 17056636) while the p.Pro34Arg substitution was reported in a patient with cardio-faciocutaneous syndrome (PMID: 16474405). This indicates that the proline residue is important for KRAS protein function. Experimental studies have shown that this missense change leads to insensitivity to GTPase-activating protein (GAP) and results in the loss of GAP-induced GTP hydrolysis capability of KRAS. Additional experiments showed mild increase in the phosphorylation of the downstream targets of KRAS (PMID: 20949621). For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157668 SCV000207634 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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