ClinVar Miner

Submissions for variant NM_004985.5(KRAS):c.13A>G (p.Lys5Glu)

dbSNP: rs193929331
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000364781 SCV000329382 pathogenic not provided 2022-05-05 criteria provided, single submitter clinical testing Identified in several patients with clinical features of Noonan syndrome in the literature and previously tested at GeneDx (Bertola et al., 2007; Quaio et al., 2013; Quaio et al., 2012); 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: 24803665, 18958496, 17056636, 17704260, 17468812, 24037001, 22488759, 22211815)
Laboratory for Molecular Medicine, Mass General Brigham 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000149836 SCV001363595 likely pathogenic RASopathy 2021-11-21 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 247720 control chromosomes. c.13A>G has been reported in the literature in individuals affected with Noonan Syndrome And Related Conditions (example, Bertola_2007, Nava_2007, Leung_2018, Yamamoto_2020, Lallar_2021). These data indicate that the variant is likely to 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as likely pathogenic. One submitter indicates a de novo occurrence in an affected individual at their laboratory and cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000149836 SCV002233973 pathogenic RASopathy 2023-12-26 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 5 of the KRAS protein (p.Lys5Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with KRAS-related conditions (PMID: 17468812, 17704260). ClinVar contains an entry for this variant (Variation ID: 12596). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function with a positive predictive value of 95%. This variant disrupts the p.Lys5 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17056636, 20949621). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000013427 SCV002766716 pathogenic Noonan syndrome 3 2020-06-11 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamic acid (exon 2). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternative change at the same residue (p.Lys5Asn) has been reported as pathogenic, and was observed in a de novo patient with a RASopathy (ClinVar, PMID: 17056636). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple patients with RASopathies (ClinVar, PMID: 29402968, PMID: 24037001, PMID: 17468812, PMID: 17704260). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Preventiongenetics, part of Exact Sciences RCV003398495 SCV004120830 pathogenic KRAS-related condition 2022-09-04 criteria provided, single submitter clinical testing The KRAS c.13A>G variant is predicted to result in the amino acid substitution p.Lys5Glu. This variant has been reported in individual with Costello syndrome and Noonan syndrome (Bertola et al. 2007. PubMed ID: 17468812; Quaio et al. 2013. PubMed ID: 24037001). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare and is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12596/). Taken together, this variant is interpreted as 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
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000364781 SCV001554431 pathogenic not provided no assertion criteria provided clinical testing
Laboratory of Virology, Oncology, Biosciences and Environment, Faculty of Sciences and Techniques, Mohammedia- University Hassan II of Casablanca RCV002291547 SCV002584823 uncertain significance Prostate cancer, hereditary, 1 2022-07-29 no assertion criteria provided clinical testing

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