ClinVar Miner

Submissions for variant NM_004985.5(KRAS):c.65A>G (p.Gln22Arg) (rs727503110)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000150893 SCV000616405 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.65A>G (p.Gln22Arg) variant in KRAS has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; Partners LMM internal data; GTR ID 21766; ClinVar SCV000198473.4). In vitro functional studies provide some evidence that the p.Gln22Arg variant may impact protein function (PS3; PMID 20652921). This variant was absent from large population studies (PM2; ExAC, The p.Gln22Arg variant has been identified in 2 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré hospital; GTR ID: 26957, 21766, 506381, 28338; ClinVar SCV000198473.4; SCV000207881.8; SCV000253709.2; SCV000207633.1). Computational prediction tools and conservation analysis suggest that the p.Gln22Arg variant may impact the protein (PP3). 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. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS3, PM2, PS4_Moderate, PP2, PP3.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150893 SCV000198473 pathogenic Noonan syndrome 2015-11-23 criteria provided, single submitter clinical testing The p.Gln22Arg variant in KRAS has been reported in 8 individuals with clinical features of a RASopathy, and occured de novo in 1 of these individuals (Zenker 2007, Gremer 2010, LMM unpublished data). It was absent from large population st udies. In vitro functional studies provide some evidence that the p.Gln22Arg var iant impacts protein function (Gremer 2010). In summary, this variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal domi nant manner based upon de novo occurrence, absence from controls, and functional evidence.
GeneDx RCV000157667 SCV000207881 pathogenic not provided 2013-07-10 criteria provided, single submitter clinical testing Heterozygous for the Q22R mutation in the KRAS gene, consistent with the diagnosis of a disorder in the Noonan syndrome spectrum.p.Gln22Arg (CAG>CGG): c.65 A>G in exon 2 of the KRAS gene (NM_004985.3)The Q22R missense mutation in the KRAS gene has been reported previously in association with severe" Noonan syndrome and has also been reported in association with somatic cancer (Zenker et al., 2007 and Aoki et al., 2008). However, the link between Q22R and somatic cancer is unclear, as this mutation was identified on the same allele in "cis" phase with the common oncogenic mutation G12S (Zenker et al., 2007 and Miyakura et al., 2002). Another missense mutation at codon 22, Q22E, has previously been reported in association with Cardio-Facio-Cutaneous syndrome (Zenker et al., 2007 and Aoki et al., 2008). The Q22R mutation 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. The variant is found in NOONAN panel(s)."
Invitae RCV000157946 SCV000253709 likely pathogenic Rasopathy 2015-05-17 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 22 of the KRAS protein (p.Gln22Arg). The arginine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in the large population databases (ExAC). It has been reported in a single sporadic case of Noonan syndrome (PMID: 17056636). However, the parents were not available for testing so it remains unknown if this variant was de novo in this individual. Experimental studies show that this missense change disrupts some but not all functional activities of the KRAS protein in vitro (PMID: 20949621). A different missense substitution at this codon (p.Gln22Glu) also disrupts protein function (PMID: 20949621) and is reported in a patient with cardio-facio-cutaneous syndrome (PMID: 17056636), which further indicates Glu22 is a critical residue. In summary, this missense variant is absent from the general population, reported in an individual with Noonan syndrome and partially disrupts protein function. For these reasons, it has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506533 SCV000604082 pathogenic not specified 2017-01-05 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000576784 SCV000678231 pathogenic Noonan syndrome 3; Cardiofaciocutaneous syndrome 2 2017-08-01 criteria provided, single submitter clinical testing KRAS NM_004985 exon2 p.Gln22Arg (c.65A>G): This variant has been identified de novo in 1 individual with Noonan syndrome (Zenker 2007 PMID: 17056636). However, the authors of this publication note that both parental samples were not available for this individual. Of note, another variant at this position (p.Gln22Glu) was identified de novo in an individual with CFC (Cardio-Facio-Cutaneous) syndrome (Zenker 2007 PMID: 17056636). This variant is absent from large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variant ID: 40452). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Gremer 2011 PMID: 20949621). In summary, this variant is classified as pathogenic based on the data above.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157667 SCV000207633 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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