rs104894360
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4PM2_SupportingPS3_ModeratePP3PP2PS2
This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256478/MONDO:0021060/044
Frequency
Consequence
NM_004985.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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KRAS | NM_004985.5 | c.458A>T | p.Asp153Val | missense_variant | Exon 5 of 5 | ENST00000311936.8 | NP_004976.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Noonan syndrome 3 Pathogenic:6
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Criteria applied: PS3,PS2_STR,PS4_SUP,PP3 -
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not provided Pathogenic:3
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) -
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RASopathy Pathogenic:2
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) -
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. -
not specified Pathogenic:1
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Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1
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). -
Cardiofaciocutaneous syndrome 2 Pathogenic:1
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Noonan syndrome 1 Pathogenic:1
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Malignant tumor of urinary bladder;C0023467:Acute myeloid leukemia;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0684249:Lung carcinoma;C0917804:Cerebral arteriovenous malformation;C1708349:Hereditary diffuse gastric adenocarcinoma;C1860991:Noonan syndrome 3;C2674723:Autoimmune lymphoproliferative syndrome type 4;C3809005:Cardiofaciocutaneous syndrome 2;C4552097:Linear nevus sebaceous syndrome Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at