Submissions for variant NM_004985.5(KRAS):c.65A>G (p.Gln22Arg)

dbSNP: rs727503110

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000157946	SCV000616405	pathogenic	RASopathy	2024-12-03	reviewed by expert panel	curation	The c.65A>G variant in the KRAS gene is a missense variant predicted to cause substitution of glutamine by arginine at amino acid 22 (p.Glln22Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.749 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). This variant has been reported in several individuals with clinical features of a RASopathy, with 2 unconfirmed de novo occurrences (PS4, PM6_VeryStrong; GeneDx, Partners LMM, HudsonAlpha Institute for Biotechnology, Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, ARUP Laboratories, Molecular Genetics and Genomics; ClinVar: SCV000207881.10; SCV000198473.4; SCV001870321.1; SCV000678231.1; SCV000604082.1). In vitro functional studies showed that this variant enhanced ERK 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: PM6_VeryStrong, PS4, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150893	SCV000198473	pathogenic	Noonan syndrome	2015-11-23	criteria provided, single submitter	clinical testing	The p.Gln22Arg variant in KRAS has been reported in 8 individuals with clinical features of a RASopathy, and occured de novo in 1 of these individuals (Zenker 2007, Gremer 2010, LMM unpublished data). It was absent from large population st udies. In vitro functional studies provide some evidence that the p.Gln22Arg var iant impacts protein function (Gremer 2010). In summary, this variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal domi nant manner based upon de novo occurrence, absence from controls, and functional evidence.
GeneDx	RCV000157667	SCV000207881	pathogenic	not provided	2024-07-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrated enhanced ERK1/2 phosphorylation (PMID: 20949621); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14982869, 24803665, 31486960, 18628094, 20652921, 12110640, 17056636, 36672771, 33057194, 35982159, 29948256, 20949621)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000157946	SCV000253709	pathogenic	RASopathy	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 22 of the KRAS protein (p.Gln22Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 17056636, 29948256; internal data). ClinVar contains an entry for this variant (Variation ID: 40452). 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.Glu22 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17056636, 17324647, 20949621, 24803665). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000506533	SCV000604082	pathogenic	not specified	2017-01-05	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000576784	SCV000678231	pathogenic	Noonan syndrome 3; Cardiofaciocutaneous syndrome 2		criteria provided, single submitter	clinical testing	KRAS NM_004985 exon2 p.Gln22Arg (c.65A>G): This variant has been identified de novo in 1 individual with Noonan syndrome (Zenker 2007 PMID: 17056636). However, the authors of this publication note that both parental samples were not available for this individual. Of note, another variant at this position (p.Gln22Glu) was identified de novo in an individual with CFC (Cardio-Facio-Cutaneous) syndrome (Zenker 2007 PMID: 17056636). This variant is absent from large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variant ID: 40452). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Gremer 2011 PMID: 20949621). In summary, this variant is classified as pathogenic based on the data above
Institute of Human Genetics, University of Leipzig Medical Center	RCV001095664	SCV001251429	pathogenic	Noonan syndrome 3	2019-10-15	criteria provided, single submitter	clinical testing	The variant was identified as de novo (maternity and paternity confirmed)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001095664	SCV001870321	pathogenic	Noonan syndrome 3	2020-05-15	criteria provided, single submitter	research	ACMG codes:PS3, PS4M, PM2, PP3, PP5
3billion	RCV001095664	SCV002318745	pathogenic	Noonan syndrome 3	2022-03-22	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040452). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20652921). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040451,VCV000040453,VCV000376325, PMID:17056636). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.749>=0.6). A missense variant is a common mechanism associated with Noonan syndrome 3. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Revvity Omics, Revvity	RCV000157667	SCV003818899	pathogenic	not provided	2022-05-20	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV005406768	SCV003920136	pathogenic	Familial cancer of breast; Noonan syndrome 3; Linear nevus sebaceous syndrome; Toriello-Lacassie-Droste syndrome; Cerebral arteriovenous malformation; Malignant tumor of urinary bladder; Autoimmune lymphoproliferative syndrome type 4; Acute myeloid leukemia; Cardiofaciocutaneous syndrome 2; Familial pancreatic carcinoma; Gastric cancer; Lung cancer		criteria provided, single submitter	clinical testing	KRAS NM_004985 exon2 p.Gln22Arg (c.65A>G): This variant has been identified de novo in 1 individual with Noonan syndrome (Zenker 2007 PMID: 17056636). However, the authors of this publication note that both parental samples were not available for this individual. Of note, another variant at this position (p.Gln22Glu) was identified de novo in an individual with CFC (Cardio-Facio-Cutaneous) syndrome (Zenker 2007 PMID: 17056636). This variant is absent from large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variant ID: 40452). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Gremer 2011 PMID: 20949621). In summary, this variant is classified as pathogenic based on the data above.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000157667	SCV000207633	pathogenic	not provided	2015-01-15	no assertion criteria provided	clinical testing