12-25245345-C-T
Variant summary
Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS2PP3PP2PM2_SupportingPS3_ModeratePS4PM1
This summary comes from the ClinGen Evidence Repository: The c.40G>A variant in the KRAS gene is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 14 (p.Val14Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.803 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 resides within a region (amino acids 10-17) of KRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). This variant has been reported in 6 individuals with two confirmed de novo occurrences with clinical features of a RASopathy (PS4, PS2_VeryStrong; PMIDs: 16474405, 17704260, 18958496, 19020799, 20949621). In vitro functional studies showed that the p.Val14Ile variant enhanced RAS/MEK/ERK activation (PS3_Moderate; PMID: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, PM1, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA156358/MONDO:0021060/044
Frequency
Consequence
NM_033360.4 missense
Scores
Clinical Significance
Conservation
Publications
- cardiofaciocutaneous syndrome 2Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
- Noonan syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Noonan syndrome 3Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- cardiofaciocutaneous syndromeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
- linear nevus sebaceous syndromeInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Costello syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 15 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00 AC: 0AN: 249502 AF XY: 0.00
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460534Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726464 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
ClinVar
Submissions by phenotype
Noonan syndrome 3 Pathogenic:9
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.
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:20949621). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.91). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012589). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 16474405) and observed in at least two similarly affected unrelated individuals (PMID:17704260, 18958496, 19020799, 20949621). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
ACMG Criteria: PS2, PS3, PS4, PM1, PM2, PP3, PP5; Variant was found in heterozygous state. De novo-status was confirmed via in-house segregation analysis.
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is the only reported mechanism of disease in this gene. This gene is associated with multiple somatic and germline conditions. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated RAS domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Criteria applied: PS2_VSTR,PS4,PS3_MOD,PM1,PM2_SUP,PP2,PP3
not provided Pathogenic:8
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.
Published functional studies demonstrate that p.(V14I) results in abnormal KRAS activity (Schubbert et al., 2006; Gremer et al., 2011); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24604757, 19020799, 26350204, 20949621, 27174785, 17056636, 17704260, 24803665, 27521173, 27884935, 29948256, 18958496, 30953504, 30050098, 29907801, 31130284, 32960281, 33318624, 17875937, 29493581, 16474405)
KRAS: PM6:Strong, PS3, PM2, PP3
RASopathy Pathogenic:2
The c.40G>A variant in the KRAS gene is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 14 (p.Val14Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.803 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 resides within a region (amino acids 10-17) of KRAS that is defined as a critical functional domain by the ClinGen RASopathy VCEP (PM1). This variant has been reported in 6 individuals with two confirmed de novo occurrences with clinical features of a RASopathy (PS4, PS2_VeryStrong; PMIDs: 16474405, 17704260, 18958496, 19020799, 20949621). In vitro functional studies showed that the p.Val14Ile variant enhanced RAS/MEK/ERK activation (PS3_Moderate; PMID: 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, PM1, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 14 of the KRAS protein (p.Val14Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with Noonan syndrome (PMID: 16474405, 17056636, 17704260, 18958496, 19020799). ClinVar contains an entry for this variant (Variation ID: 12589). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KRAS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KRAS function (PMID: 16474405, 17875937, 20949621, 24803665, 25359213). For these reasons, this variant has been classified as Pathogenic.
Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1
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.
Cardiovascular phenotype Pathogenic:1
The c.40G>A (p.V14I) alteration is located in exon 2 (coding exon 1) of the KRAS gene. This alteration results from a G to A substitution at nucleotide position 40, causing the valine (V) at amino acid position 14 to be replaced by an isoleucine (I). The Genome Aggregation Database (gnomAD) data for this variant is unreliable due to technical and/or biological issues, therefore population frequency estimates were not considered. This variant was reported in individual(s) with features consistent with KRAS-related RASopathy; in at least one individual, it was determined to be de novo (Schubbert, 2006; Zenker, 2007; Nava, 2007; Ko, 2008; Lo, 2009; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that protein containing the p.V14I alteration has an increased rate of the GDP/GTP exchange which resulted in an accumulation of protein in the GTP-bound state and a moderate increase in downstream signaling. In addition, protein with this mutation also showed decrease of binding affinity to RAF1-RBD and RALGDS-RBD (Gremer, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Endometrial carcinoma Other:1
Computational scores
Source:
Splicing
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