ClinVar Miner

Submissions for variant NM_033360.4(KRAS):c.13A>G (p.Lys5Glu) (rs193929331)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000364781 SCV000329382 likely pathogenic not provided 2016-04-13 criteria provided, single submitter clinical testing The K5E variant in the KRAS gene has been published previously in multiple patients with Noonan specutrum disorders (Bertola et al., 2007; Nava et al., 2007; Bertola 2012; Quaio et al., 2013). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. K5E is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Another missense change at the same residue (K5N) has been reported in the Human Gene Mutation Database in association with Costello syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In addition, the KRAS gene has a low rate of benign missense variation, with missense variants being a common mechanism of disorder. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000605141 SCV000710866 likely pathogenic Noonan syndrome 2016-09-09 criteria provided, single submitter clinical testing The p.Lys5Glu variant in KRAS has been reported in 3 individuals with clinical f eatures of a RASopathy disorder and one was observed to have occurred de novo (B ertola 2007, Nava 2007, LMM data). This variant was absent from large population studies. Another change at this position (p.Lys5Asn) was identified as a de nov o variant in one individual with features of a RASopathy, suggesting changes at this position are not tolerated. Computational prediction tools and conservation analysis suggest that the p.Lys5Glu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, al though additional studies are required to fully establish its clinical significa nce, the p.Lys5Glu variant is likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000149836 SCV001363595 likely pathogenic Rasopathy 2019-02-12 criteria provided, single submitter clinical testing Variant summary: KRAS c.13A>G (p.Lys5Glu) results in a conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 236356 control chromosomes (gnomAD). c.13A>G has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Bertola 2007, Nava 2007). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant affecting the same amino acid (K5N) has been reported in HGMD in association with Costello syndrome, supporting the functional importance of this amino acid residue. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic. One submitter, LMM, indicates a de novo occurrence in an affected individual. Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM RCV000013427 SCV000033674 pathogenic Noonan syndrome 3 2012-06-01 no assertion criteria provided literature only
Baylor Genetics RCV000149836 SCV000196680 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines

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