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

dbSNP: rs104894360

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
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
Invitae	RCV000157940	SCV000659087	pathogenic	RASopathy	2023-08-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KRAS function (PMID: 16474404, 20949621). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 12587). 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. This variant is not present in population databases (gnomAD no frequency). 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).
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	RCV001267227	SCV001445408	pathogenic	Inborn genetic diseases	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
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
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