rs193929331
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_004985.5(KRAS):āc.13A>Gā(p.Lys5Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K5N) has been classified as Pathogenic.
Frequency
Consequence
NM_004985.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRAS | NM_033360.4 | c.13A>G | p.Lys5Glu | missense_variant | 2/6 | ENST00000256078.10 | |
KRAS | NM_004985.5 | c.13A>G | p.Lys5Glu | missense_variant | 2/5 | ENST00000311936.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRAS | ENST00000256078.10 | c.13A>G | p.Lys5Glu | missense_variant | 2/6 | 1 | NM_033360.4 | A1 | |
KRAS | ENST00000311936.8 | c.13A>G | p.Lys5Glu | missense_variant | 2/5 | 1 | NM_004985.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459620Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 725946
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
RASopathy Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | - | Variant classified using ACMG guidelines - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 21, 2021 | Variant summary: KRAS c.13A>G (p.Lys5Glu) results in a conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247720 control chromosomes. c.13A>G has been reported in the literature in individuals affected with Noonan Syndrome And Related Conditions (example, Bertola_2007, Nava_2007, Leung_2018, Yamamoto_2020, Lallar_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant affecting the same amino acid (K5N) has been reported in HGMD in association with Costello syndrome, supporting the functional importance of this amino acid residue. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as likely pathogenic. One submitter indicates a de novo occurrence in an affected individual at their laboratory and cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2023 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 5 of the KRAS protein (p.Lys5Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with KRAS-related conditions (PMID: 17468812, 17704260). ClinVar contains an entry for this variant (Variation ID: 12596). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function with a positive predictive value of 95%. This variant disrupts the p.Lys5 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17056636, 20949621). 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. - |
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2022 | Identified in several patients with clinical features of Noonan syndrome in the literature and previously tested at GeneDx (Bertola et al., 2007; Quaio et al., 2013; Quaio et al., 2012); Missense variants in this gene are often considered pathogenic (HGMD); 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); This variant is associated with the following publications: (PMID: 24803665, 18958496, 17056636, 17704260, 17468812, 24037001, 22488759, 22211815) - |
Noonan syndrome 3 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 11, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from lysine to glutamic acid (exon 2). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0704 - Comparable variant has low previous evidence for pathogenicity. An alternative change at the same residue (p.Lys5Asn) has been reported as pathogenic, and was observed in a de novo patient with a RASopathy (ClinVar, PMID: 17056636). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple patients with RASopathies (ClinVar, PMID: 29402968, PMID: 24037001, PMID: 17468812, PMID: 17704260). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2012 | - - |
KRAS-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 04, 2022 | The KRAS c.13A>G variant is predicted to result in the amino acid substitution p.Lys5Glu. This variant has been reported in individual with Costello syndrome and Noonan syndrome (Bertola et al. 2007. PubMed ID: 17468812; Quaio et al. 2013. PubMed ID: 24037001). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare and is interpreted as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12596/). Taken together, this variant is interpreted as pathogenic. - |
Noonan syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 09, 2016 | The p.Lys5Glu variant in KRAS has been reported in 3 individuals with clinical f eatures of a RASopathy disorder and one was observed to have occurred de novo (B ertola 2007, Nava 2007, LMM data). This variant was absent from large population studies. Another change at this position (p.Lys5Asn) was identified as a de nov o variant in one individual with features of a RASopathy, suggesting changes at this position are not tolerated. Computational prediction tools and conservation analysis suggest that the p.Lys5Glu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, al though additional studies are required to fully establish its clinical significa nce, the p.Lys5Glu variant is likely pathogenic. - |
Prostate cancer, hereditary, 1 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Virology, Oncology, Biosciences and Environment, Faculty of Sciences and Techniques, Mohammedia- University Hassan II of Casablanca | Jul 29, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at