12-25245284-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM5PS2PM2PP2PP3
This summary comes from the ClinGen Evidence Repository: The c.101C>T (p.Pro34Leu) variant in KRAS has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2; PMID 17056636, 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). A different pathogenic missense variant has been previously identified at this codon of KRAS which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 12590). Computational prediction tools and conservation analysis suggest that the p.Pro34Leu variant may impact the protein (PP3; PMID:24803665). 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; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PS2, PM2, PM5, PP3, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA235301/MONDO:0018997/004
Frequency
Consequence
NM_004985.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRAS | NM_033360.4 | c.101C>T | p.Pro34Leu | missense_variant | 2/6 | ENST00000256078.10 | |
KRAS | NM_004985.5 | c.101C>T | p.Pro34Leu | missense_variant | 2/5 | ENST00000311936.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRAS | ENST00000256078.10 | c.101C>T | p.Pro34Leu | missense_variant | 2/6 | 1 | NM_033360.4 | A1 | |
KRAS | ENST00000311936.8 | c.101C>T | p.Pro34Leu | missense_variant | 2/5 | 1 | NM_004985.5 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 15, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 21, 2012 | The P34L missense mutation in the KRAS gene has been reported previously in association with Noonan syndrome (Zenker et al., 2007). Other missense mutations at the same codon (P34Q and P34R) have been reported in association with KRAS-related disorders (Zenker et al., 2007; Schubbert et al., 2006). Therefore, its presence is consistent with a diagnosis of a KRAS-related disorder. The variant is found in NOONAN panel(s). - |
Noonan syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 04, 2013 | The Pro34Leu variant in KRAS has not been identified by our laboratory, but has been reported in one individual with Noonan syndrome where it was demonstrated t o have occurred de novo (Zenker 2007). Another variant at the same nucleotide p osition (c.101C>A, p.Pro34Gln) has also been reported in another patient with No onan syndrome where it too, was demonstrated to have occurred de novo (Zenker 20 07). Functional studies have shown that the Pro34Leu variant results in a GTPas e-Activating Protein (GAP)-resistant conformation and consequently, to a weak ga in-of-function, consistent with disease pathogenesis (Gremer 2010). This variant has not been reported in large population studies, consistent with a pathogenic role. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may impact the protein. In summary, this variant meets our criteria to be classified as pathogenic bas ed on the de novo occurrence and supportive functional studies (http://pcpgm.par tners.org/LMM). - |
Pathogenic, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The c.101C>T (p.Pro34Leu) variant in KRAS has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2; PMID 17056636, 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). A different pathogenic missense variant has been previously identified at this codon of KRAS which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 12590). Computational prediction tools and conservation analysis suggest that the p.Pro34Leu variant may impact the protein (PP3; PMID: 24803665). 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; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PS2, PM2, PM5, PP3, PP2. - |
Noonan syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics, Centre for Human Genetics | - | - - |
Noonan syndrome 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040454). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 17056636, 20949621). A different missense change at the same codon (p.Pro34Arg) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012590). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 09, 2016 | This sequence change replaces proline with leucine at codon 34 of the KRAS protein (p.Pro34Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (rs104894366, ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change leads to insensitivity to GTPase-activating protein (GAP) and results in the loss of GAP-induced GTP hydrolysis capability of KRAS. Additional experiments showed  mild increase in the phosphorylation of the downstream targets of KRAS (PMID: 20949621). Two other missense substitution at this codon (p.Pro34Arg and p.Pro34Gln) have also been shown to arise de novo in individuals affected with KRAS-related disorders. The p.Pro34Gln substitution was reported in a patient affected with Noonan syndrome (PMID: 17056636) while the p.Pro34Arg substitution was reported in a patient with cardio-faciocutaneous syndrome (PMID: 16474405). This indicates that the proline residue is important for KRAS protein function. This variant has been shown to arise de novo in individuals affected with Noonan syndrome (PMID: 17056636). ClinVar contains an entry for this variant (Variation ID: 40454). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at