ClinVar Miner

Submissions for variant NM_004985.5(KRAS):c.458A>T (p.Asp153Val) (rs104894360)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507330 SCV000604083 pathogenic not specified 2017-04-20 criteria provided, single submitter clinical testing
Baylor Genetics RCV000013418 SCV000854617 pathogenic Noonan syndrome 3 2018-11-18 no assertion criteria provided clinical testing
Blueprint Genetics RCV000212501 SCV000927902 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing
ClinGen RASopathy Variant Curation Expert Panel RCV000523200 SCV000616371 pathogenic Noonan syndrome 2018-11-15 reviewed by expert panel curation The c.458A>T (p.Asp153Val) 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; PMID 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). In vitro functional studies provide some evidence that the p.Asp153Val variant may impact protein function (PS3; PMID 20949621). The p.Asp153Val variant in KRAS has been reported in the literature in at least 4 patients with clinical features of a RASopathy (PS4_Moderate; LMM internal data GTR Lab ID: 21766, ClinVar SCV000203924.4; PMID 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). 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, PS4_Moderate.
Fulgent Genetics,Fulgent Genetics RCV000763307 SCV000893975 pathogenic Familial cancer of breast; Hereditary diffuse gastric cancer; Lung cancer; Noonan syndrome 3; Epidermal nevus syndrome; Cerebral arteriovenous malformation; Bladder cancer, somatic; Carcinoma of pancreas; RAS-associated autoimmune leukoproliferative disorder; Acute myeloid leukemia; Cardiofaciocutaneous syndrome 2 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000212501 SCV000207875 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing This variant has been published previously as apparently de novo in association with Noonan and cardio-facio-cutaneous syndromes (Carta et al., 2006; Schubbert et al., 2006; Niihori et al., 2006). The variant is not observed in large population cohorts (Lek et al., 2016). D153V 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Functional studies have shown that D153V increases the activity of the KRAS protein compared to wild type (Mazhab-Jafari et al., 2015). In summary, we consider this variant to be pathogenic.
Invitae RCV000157940 SCV000659087 pathogenic Rasopathy 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 153 of the KRAS protein (p.Asp153Val). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (rs104894360, ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome or cardiofaciocutaneous syndrome (PMID: 24703799, 21062266, 21871821, 18456719, 17056636). In at least 2 individuals, this variant was reported to be de novo (PMID: 16773572, 16474405). ClinVar contains an entry for this variant (Variation ID: 12587). Experimental studies have shown that this missense change results in increased KRAS activity (PMID: 20949621, 16474404). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000844634 SCV000203924 pathogenic Noonan syndrome; Cardio-facio-cutaneous syndrome 2014-05-12 criteria provided, single submitter clinical testing The Asp153Val variant has been associated with the clinical features of Noonan s yndrome and Cardio-facio-cutaneous syndrome (CFC; Nystrom 2008, Schubbert 2007, Tang 2007, Zenker 2007, Carta 2006, Niihori 2006, Schubbert 2006). In several of these individuals the variant was shown to have occurred de novo. In summary, t his variant meets our criteria to be classified as pathogenic (http://pcpgm.part ners.org/LMM).
OMIM RCV000013417 SCV000033664 pathogenic Cardiofaciocutaneous syndrome 2 2006-03-01 no assertion criteria provided literature only
OMIM RCV000013418 SCV000033665 pathogenic Noonan syndrome 3 2019-07-23 no assertion criteria provided literature only
UCLA Clinical Genomics Center, UCLA RCV000013418 SCV000255402 pathogenic Noonan syndrome 3 2013-03-12 criteria provided, single submitter clinical testing

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