Submissions for variant NM_004985.5(KRAS):c.108A>G (p.Ile36Met)

dbSNP: rs727503109

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized 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
GeneDx	RCV000260877	SCV000329772	likely pathogenic	not provided	2022-12-20	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 30586318, 18470943, 21784453, 24803665, 25525159, 17056636, 18958496, 29493581, 35158933, 32240795, 17211612, 27104176)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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
Invitae	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, University Hospital Bonn	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.
PreventionGenetics, part of Exact Sciences	RCV003945189	SCV004759872	pathogenic	KRAS-related condition	2023-11-04	criteria provided, single submitter	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.
Gharavi Laboratory, Columbia University	RCV000260877	SCV000809220	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000260877	SCV001808517	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000260877	SCV001952076	pathogenic	not provided		no assertion criteria provided	clinical testing