ClinVar Miner

Submissions for variant NM_004985.5(KRAS):c.101C>G (p.Pro34Arg) (rs104894366)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211723 SCV000061924 likely pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2015-08-21 criteria provided, single submitter clinical testing The p.Pro34Arg in KRAS variant has been reported 1 adolescent with clinical feat ures of Cardio-facio-cutaneous syndrome as a de novo occurrence (Schubbert 2006) and by our laboratory in 1 child with clinical features of Noonan syndrome (LMM unpublished data). It was absent from large population studies. In vitro functi onal studies provide evidence that the p.Pro34Arg may impact protein function (S tone 1993, Schubbert 2007, Gremer 2010). However, these types of assays may not accurately represent biological function. In summary, although additional studie s are required to fully establish its clinical significance, the p.Pro34Arg vari ant is likely pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000207495 SCV000263050 pathogenic not provided 2015-07-20 criteria provided, single submitter clinical testing
GeneDx RCV000207495 SCV000329384 pathogenic not provided 2017-12-11 criteria provided, single submitter clinical testing The P34R variant in the KRAS gene has been reported previously in an adolescent girl with a clinical diagnosis of cardio-facio-cutaneous syndrome (Schubbert et al., 2006). The P34R variant is not observed in large population cohorts (Lek et al., 2016). The P34R variant is a non-conservative amino acid substitution, which occurs at a position within the GTP nucleotide binding region, is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In vitro functional assays demonstrate that this variant results in increased GTP hydrolysis and constitutive phosphorylation of downstream targets, suggesting this variant is likely to result in a gain of function (Schubbert et al., 2007; Gremer et al., 2011). Additionally, other missense variants at this same residue (P34Q, P34L) and in a nearby residue (I36M) have been reported in the Human Gene Mutation Database in association with features of cardio-facio-cutaneous syndrome and Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret P34R as a pathogenic variant.
Baylor Genetics RCV000850569 SCV000992785 pathogenic Noonan syndrome 3; RAS-associated autoimmune leukoproliferative disorder; Acute myeloid leukemia; Cardiofaciocutaneous syndrome 2 2017-12-31 criteria provided, single submitter clinical testing
OMIM RCV000043674 SCV000033668 pathogenic Cardiofaciocutaneous syndrome 2 2006-03-01 no assertion criteria provided literature only

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