Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000844636 | SCV000198471 | likely pathogenic | Noonan syndrome; Cardio-facio-cutaneous syndrome | 2018-02-15 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
Gene |
RCV000260877 | SCV000329772 | likely pathogenic | not provided | 2024-10-23 | criteria provided, single submitter | clinical testing | 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; 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: 18470943, 21784453, 24803665, 25525159, 18958496, 29493581, 17056636, 30586318, 32240795, 35158933, 17211612, 27104176, 37434678, 36066546, 37065036, 38339343) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000150891 | SCV000919564 | likely pathogenic | RASopathy | 2018-10-25 | criteria provided, single submitter | clinical testing | Variant summary: KRAS c.108A>G (p.Ile36Met) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) 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 237482 control chromosomes (gnomAD). c.108A>G has been reported in the literature in individuals affected with Noonan Syndrome (Zenker 2007, Lo 2009, Lee 2011). 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; though an in vitro study demonstrated that substitutions of Ile36 caused severe impairment in Ras protein function, indicating the importance of this amino acid residue (Chung 1993). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic (1x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Blueprint Genetics | RCV000260877 | SCV000927544 | likely pathogenic | not provided | 2018-02-23 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000150891 | SCV000939441 | pathogenic | RASopathy | 2022-10-01 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 36 of the KRAS protein (p.Ile36Met). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 163768). This missense change has been observed in individual(s) with RASopathies spectrum (PMID: 17056636, 18958496, 21784453; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). |
Institute for Genomic Statistics and Bioinformatics, |
RCV000856729 | SCV000999274 | pathogenic | Cardiofaciocutaneous syndrome 1 | criteria provided, single submitter | clinical testing | ||
Ambry Genetics | RCV002444616 | SCV002733242 | pathogenic | Cardiovascular phenotype | 2017-02-01 | criteria provided, single submitter | clinical testing | The p.I36M pathogenic mutation (also known as c.108A>G), located in coding exon 1 of the KRAS gene, results from an A to G substitution at nucleotide position 108. The isoleucine at codon 36 is replaced by methionine, an amino acid with similar properties. This variant has been reported in two unrelated individuals with clinical diagnoses of Noonan syndrome (Zenker M et al. J Med Genet. 2007;44(2):131-5; Lo FS et al. Eur J Pediatr. 2009;168(8):919-23). This amino acid substitution resulted in decreased GAP activation in vitro (Chung HH et al. Proc Natl Acad Sci U S A. 1993;90(21):10145-9). In addition, this mutation has been determined by our laboratory to be the result of a de novo event in one family in the setting of new disease. Based on the supporting evidence, p.I36M is interpreted as a disease-causing mutation. |
Gharavi Laboratory, |
RCV000260877 | SCV000809220 | pathogenic | not provided | 2018-09-16 | no assertion criteria provided | research | |
Genome Diagnostics Laboratory, |
RCV000260877 | SCV001808517 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000260877 | SCV001952076 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Prevention |
RCV004551310 | SCV004759872 | pathogenic | KRAS-related disorder | 2023-11-04 | no assertion criteria provided | clinical testing | The KRAS c.108A>G variant is predicted to result in the amino acid substitution p.Ile36Met. This variant has been reported as a recurrent finding in individuals with Noonan syndrome (Zenker et al. 2007. PubMed ID: 17056636; Lo et al. 2009. PubMed ID: 18958496; Lee et al. 2011. PubMed ID: 21784453). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. |