ClinVar Miner

Submissions for variant NM_004985.5(KRAS):c.40G>A (p.Val14Ile) (rs104894365)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000521254 SCV000616367 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.40G>A (p.Val14Ile) variant in KRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 16474405). The p.Val14Ile variant has been identified in at least 4 independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; PMID: 20949621, 19020799, 18958496, 17704260). In vitro functional studies provide some evidence that the p.Val14Ile variant may impact protein function (PS3; PMID: 20949621). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of KRAS (PM1; PMID 29493581). 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). Computational prediction tools and conservation analysis suggest that the p.Val14Ile variant may impact the protein (PP3). 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): PS2_VeryStrong, PS4_Moderate, PS3, PM1, PP2, PP3).
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844637 SCV000203925 pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2014-05-06 criteria provided, single submitter clinical testing The p.Val14Ile variant in KRAS has been reported in >10 individuals with clinica l features of Noonan syndrome or Cardio-facio-cutaneous syndrome, CFC (Ko 2008, Lo 2008, Gremer 2010, Nava 2007, Schubbert 2006, Zenker 2007, LMM data). This v ariant occurred de novo in at least 5 of these individuals. In addition, functio nal studies show this variant causes a gain-of-function (Schubbert 2006, Gremer 2010), an established pathogenic mechanism in Noonan spectrum disorders. Therefo re, this variant meets our criteria to be pathogenic for Noonan syndrome and CFC in an autosomal dominant manner based on de novo occurrences and functional stu dies.
GeneDx RCV000212499 SCV000207880 pathogenic not provided 2018-11-07 criteria provided, single submitter clinical testing The V14I variant in the KRAS gene has been reported previously in multiple unrelated individuals with Noonan syndrome (Schubbert et al., 2006; Nava et al., 2007; Zenker et al., 2007; Ko et al., 2008) and observed de novo in patients tested at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016). The V14I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In vitro functional studies have shown that V14I results in abnormal KRAS activity (Schubbert et al., 2006; Gremer et al., 2011). We interpret V14I as a pathogenic variant.
Invitae RCV000157945 SCV000552098 pathogenic Rasopathy 2020-10-11 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 14 of the KRAS protein (p.Val14Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs104894365, ExAC 0.002%). This variant has been reported in numerous individuals with features of Noonan syndrome, several of which were described as de novo events (PMID: 16474405, 17056636, 17704260, 18958496, 19020799). ClinVar contains an entry for this variant (Variation ID: 12589). Experimental studies have shown that this missense change results in increased KRAS activity (PMID: 16474405, 20949621, 17875937, 24803665, 25359213). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000013420 SCV000699772 pathogenic Noonan syndrome 3 2016-04-04 criteria provided, single submitter clinical testing Variant summary: c.40G>A affects a conserved nucleotide, resulting in amino acid change from Val to Ile. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant was found in 1/102298 control chromosomes at a frequency of 0.0000098, which does not exceed maximal expected frequency of a pathogenic allele (0.0000125). This variant has been reported in multiple NS patients and functional studies showed changes on the GDP/GTP exchange function (dramatic increase of variant both in its intrinsic and GEFcatalyzed nucleotide exchange) as well as impaired RAF-RBD binding ability (Gremer_HM_2011). In addition, multiple clinical laboratories and reputable databases classified this variant as pathogenic. Taken together, this variant was classified as a Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212499 SCV001248877 pathogenic not provided 2020-07-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001266727 SCV001444904 pathogenic Inborn genetic diseases 2018-11-05 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000212499 SCV001448020 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286472 SCV001473048 pathogenic none provided 2020-05-29 criteria provided, single submitter clinical testing The KRAS c.40G>A; p.Val14Ile variant (rs104894365) has been reported in several individuals with clinical features of Noonan syndrome, including instances of the variant occurring de novo (Ko 2008, Nava 2007, Schubbert 2006, Zenker 2007). The variant is described as pathogenic by several sources in the ClinVar database (Variation ID: 12589) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 14 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In support of this prediction, experimental studies have shown that this variant results in increased KRAS activity and a mouse model of this variant recapitulates Noonan syndrome (Schubbert 2006, Gremer 2011, Hernandez-Porras 2014). Considering available information, this variant is classified as pathogenic. References: Gremer L et al. Germline KRAS Mutations Cause Aberrant Biochemical and Physical Properties Leading to Developmental Disorders. Hum Mutat. 2011 Jan;32(1):33-43. Hernandez-Porras I et al. K-RasV14I Recapitulates Noonan Syndrome in Mice Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16395-400. Ko JM et al. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008;53(11-12):999-1006. Nava C et al. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. J Med Genet. 2007 Dec;44(12):763-71. Schubbert S et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006 Mar;38(3):331-6. Zenker M et al. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet. 2007 Feb;44(2):131-5.
Baylor Genetics RCV000013420 SCV001523349 pathogenic Noonan syndrome 3 2019-12-03 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM RCV000013420 SCV000033667 pathogenic Noonan syndrome 3 2006-03-01 no assertion criteria provided literature only
Laboratory of Translational Genomics, National Cancer Institute RCV000119792 SCV000154264 not provided Endometrial carcinoma no assertion provided not provided
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212499 SCV001554294 uncertain significance not provided no assertion criteria provided clinical testing

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