rs104894366
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5PS3_SupportingPS2PP3PP2PM2_SupportingPS4_Moderate
This summary comes from the ClinGen Evidence Repository: The c.101C>T variant in the KRAS gene is a missense variant predicted to cause substitution of proline by leucine at amino acid 34 (p.Pro34Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.867 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). A different pathogenic missense variant has been previously identified at this codon of KRAS (c.101C>G (p.Pro34Arg)) which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 12590). This variant has been reported in 3 individuals as two confirmed de novo occurrences and one unconfirmed de novo occurrence with clinical features of a RASopathy (PS4_Moderate, PS2_VeryStrong; PMIDs: 17056636, 30732632, ClinVar SCV: SCV000207884.10, Internal lab contributors: GeneDx). A RAS activation assay showed that this variant led to increased RAS activation (PS3_Supporting; 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_Moderate, PM5, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 09/17/2024) 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 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| KRAS | NM_004985.5 | c.101C>T | p.Pro34Leu | missense_variant | Exon 2 of 5 | ENST00000311936.8 | NP_004976.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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Published functional studies demonstrate a damaging effect on protein function (PMID: 20949621); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 29493581, 24803665, 31219622, 36566191, 36307859, 30732632, 17056636, 20949621) -
Noonan syndrome Pathogenic:2
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). -
The c.101C>T variant in the KRAS gene is a missense variant predicted to cause substitution of proline by leucine at amino acid 34 (p.Pro34Leu). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.867 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). A different pathogenic missense variant has been previously identified at this codon of KRAS (c.101C>G (p.Pro34Arg)) which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 12590). This variant has been reported in 3 individuals as two confirmed de novo occurrences and one unconfirmed de novo occurrence with clinical features of a RASopathy (PS4_Moderate, PS2_VeryStrong; PMIDs: 17056636, 30732632, ClinVar SCV: SCV000207884.10, Internal lab contributors: GeneDx). A RAS activation assay showed that this variant led to increased RAS activation (PS3_Supporting; 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_Moderate, PM5, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 09/17/2024) -
Noonan syndrome 1 Pathogenic:1
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Noonan syndrome 3 Pathogenic:1
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
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 34 of the KRAS protein (p.Pro34Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17056636). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40454). 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: 20949621). This variant disrupts the p.Pro34 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16474405, 17056636). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at