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

dbSNP: rs104894360

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000157940	SCV000616371	pathogenic	RASopathy	2024-12-03	reviewed by expert panel	curation	The c.458A>T variant in the KRAS gene is a missense variant predicted to cause substitution of asparagine by valine at amino acid 153 (p.Asp153Val). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.791 supporting a deleterious impact to KRAS function (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). This variant has been reported in at least 6 individuals with four confirmed de novo occurrences with clinical features of a RASopathy (PS4, PS2_VeryStrong; PMIDs: 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). In vitro functional studies showed that this variant enhanced RAS/MEK/ERK activation (PS3_Moderate; PMID: 17875937, 20949621). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024)
Laboratory for Molecular Medicine, Mass General Brigham 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).
GeneDx	RCV000212501	SCV000207875	pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing	Published functional studies have demonstrated that D153V increases the activity of the KRAS protein compared to wild type (Mazhab-Jafari et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20648242, 17551339, 17056636, 20949621, 24703799, 21871821, 16474405, 16474404, 16987887, 16773572, 17875937, 24803665, 21062266, 29025208, 30732632, 30138938, 30692697, 31219622, 31292302, 36028527, 18456719, 34358384, 25941399)
UCLA Clinical Genomics Center, UCLA	RCV000013418	SCV000255402	pathogenic	Noonan syndrome 3	2013-03-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507330	SCV000604083	pathogenic	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000157940	SCV000659087	pathogenic	RASopathy	2024-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 153 of the KRAS protein (p.Asp153Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome or cardiofaciocutaneous syndrome (PMID: 16474405, 16773572, 17056636, 18456719, 21062266, 21871821, 24703799). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12587). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt KRAS function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KRAS function (PMID: 16474404, 20949621). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763307	SCV000893975	pathogenic	Familial cancer of breast; Hereditary diffuse gastric adenocarcinoma; Lung carcinoma; Noonan syndrome 3; Linear nevus sebaceous syndrome; Cerebral arteriovenous malformation; Malignant tumor of urinary bladder; Carcinoma of pancreas; Autoimmune lymphoproliferative syndrome type 4; Acute myeloid leukemia; Cardiofaciocutaneous syndrome 2	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000212501	SCV000927902	pathogenic	not provided	2018-08-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018621	SCV001445408	pathogenic	Cardiovascular phenotype	2022-09-08	criteria provided, single submitter	clinical testing	The c.458A>T (p.D153V) alteration is located in exon 5 (coding exon 4) of the KRAS gene. This alteration results from an A to T substitution at nucleotide position 458, causing the aspartic acid (D) at amino acid position 153 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple unrelated individuals with features of Noonan syndrome and/or cardiofaciocutaneous syndrome. This variant occurred de novo in the majority of these individuals (Carta, 2006; Niihori, 2006; Schubbert, 2006; Zenker, 2007). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies suggest that p.D153V increases activation of MAPK signaling pathway (Niihori, 2006; Gremer, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Revvity Omics, Revvity	RCV000212501	SCV002016399	pathogenic	not provided	2021-06-26	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000013418	SCV004100759	pathogenic	Noonan syndrome 3	2023-10-09	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS2_STR,PS4_SUP,PP3
Genomic Medicine Lab, University of California San Francisco	RCV000013418	SCV004847139	pathogenic	Noonan syndrome 3	2023-08-30	criteria provided, single submitter	clinical testing
OMIM	RCV000013417	SCV000033664	pathogenic	Cardiofaciocutaneous syndrome 2	2006-03-01	no assertion criteria provided	literature only
OMIM	RCV000013418	SCV000033665	pathogenic	Noonan syndrome 3	2006-03-01	no assertion criteria provided	literature only
Baylor Genetics	RCV000013418	SCV000854617	pathogenic	Noonan syndrome 3	2018-11-18	no assertion criteria provided	clinical testing
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	RCV000013418	SCV003844090	pathogenic	Noonan syndrome 3	2021-12-24	no assertion criteria provided	research
Molecular Genetics, Centre for Human Genetics	RCV003450634	SCV004190107	pathogenic	Noonan syndrome 1		no assertion criteria provided	clinical testing