Submissions for variant NM_005343.4(HRAS):c.34G>T (p.Gly12Cys)

dbSNP: rs104894229

Total submissions: 39

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000013447	SCV000062132	pathogenic	Costello syndrome	2012-11-20	criteria provided, single submitter	clinical testing	The Gly12Cys variant in HRAS has been reported in the literature in six individu als with severe neonatal Costello syndrome (Kerr 2006, Lo 2008, Lin 2009, Niihor i 2011, Lorenz 2012). This variant has been reported to have occurred de novo in one proband (Lorenz 2012). Several other DNA variants affecting codon 12 of HRA S are commonly observed in patients with Costello syndrome (Niihori 2011). There fore, this variant is highly likely to be pathogenic.
GeneDx	RCV000212495	SCV000207843	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Published functional studies of the G12C variant have shown that it results in increased active, GTP-bound HRAS (Niihori et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 16443854, 24224811, 23093928, 24803665, 31394527, 22926243, 21850009, 16155195, 18039947, 33258288, 29493581)
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000013447	SCV000263053	pathogenic	Costello syndrome	2014-06-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762849	SCV000893209	pathogenic	Large congenital melanocytic nevus; Linear nevus sebaceous syndrome; Malignant tumor of urinary bladder; Costello syndrome; Epidermal nevus; Thyroid cancer, nonmedullary, 2	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000212495	SCV000927854	pathogenic	not provided	2018-08-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212495	SCV001247463	pathogenic	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000013447	SCV001448594	pathogenic	Costello syndrome	2020-11-09	criteria provided, single submitter	clinical testing	Variant summary: HRAS c.34G>T (p.Gly12Cys) results in a non-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 250294 control chromosomes (gnomAD). c.34G>T has been reported in the literature in multiple individuals affected with Costello Syndrome (e.g. Niihori_2011, McCormick_2013, Choi_2019). These data indicate that the variant is very likely to be associated with disease. In functional studies, Niihori et al (Niihori_2011) report that there was an increase in guanosine triphosphate (GTP)-bound HRAS and activation of RAS signaling pathway (as measured by the activation of ELK1 and c-Jun) in cells transfected with the variant of interest. In addition, HGMD database reports several other missense variants affecting the same codon and nearby codons (e.g. p.G12R, p.G12S, p.G12V, p.G12A, p.G13D, p.G13C) suggesting this area might be a mutational hotspot. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Breda Genetics srl	RCV000013447	SCV002587819	pathogenic	Costello syndrome	2022-09-21	criteria provided, single submitter	clinical testing	The variant in c.34G>T (p.Gly12Cys) in HRAS gene is reported as pathogenic for Costello syndrome and other HRAS-related diseases in ClinVar (Variation ID: 12613) and in the Global Variome shared LOVD database v.3.0 (genomic variant: #0000345686). There is no information on frequency in gnomAD or 1000 Genomes Project. The variant has been reported in in multiple individuals affected with Costello Syndrome (Choi et al., 2019, PMID: 31394527; McCormick et al., 2013, PMID: 23429430; Niihori et al., 2011, PMID: 21850009).
Invitae	RCV000013447	SCV003253337	pathogenic	Costello syndrome	2022-04-07	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 12 of the HRAS protein (p.Gly12Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Costello syndrome (PMID: 16443854, 18039947, 22926243). ClinVar contains an entry for this variant (Variation ID: 12613). 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 HRAS protein function. Experimental studies have shown that this missense change affects HRAS function (PMID: 21850009). This variant disrupts the p.Gly12 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). 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	RCV000212495	SCV004562717	pathogenic	not provided	2023-10-06	criteria provided, single submitter	clinical testing	The HRAS c.34G>T; p.Gly12Cys variant (rs104894229; ClinVar Variation ID: 12613) is reported in the literature as a recurrent de novo variant in multiple individuals affected with Costello syndrome (Choi 2019, Kerr 2006, Lorenz 2012). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine residues at codons 12 and 13 are frequently altered in both Costello syndrome patients (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011). Functional characterization of the p.Gly12Cys protein indicates increased downstream MEK signaling activity (Niihori 2011), consistent with the established disease mechanism of Costello syndrome. Based on available information, this variant is considered to be pathogenic. References: Choi N et al. Phenotypic and Genetic Characteristics of Five Korean Patients with Costello Syndrome. Cytogenet Genome Res. 2019;158(4):184-191. PMID: 31394527. Kerr B et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006 May;43(5):401-5. PMID: 16443854 Lorenz S et al Two cases with severe lethal course of Costello syndrome associated with HRAS p.G12C and p.G12D. Eur J Med Genet. 2012 Nov;55(11):615-9. PMID: 22926243. Niihori T et al. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. J Hum Genet. 2011 Oct;56(10):707-15. PMID: 21850009.
OMIM	RCV000013447	SCV000033694	pathogenic	Costello syndrome	2012-06-10	no assertion criteria provided	literature only
OMIM	RCV000029211	SCV000051857	pathogenic	Nevus sebaceous	2012-06-10	no assertion criteria provided	literature only
OMIM	RCV000032851	SCV000056620	pathogenic	Epidermal nevus	2012-06-10	no assertion criteria provided	literature only
Baylor Genetics	RCV000149829	SCV000196673	pathogenic	RASopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
Database of Curated Mutations (DoCM)	RCV000440052	SCV000505663	likely pathogenic	Urinary bladder carcinoma	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439243	SCV000506496	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422023	SCV000506497	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431815	SCV000506498	likely pathogenic	Nasopharyngeal neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444512	SCV000506499	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424380	SCV000506500	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431602	SCV000506501	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443678	SCV000506502	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427213	SCV000506503	likely pathogenic	Papillary renal cell carcinoma, sporadic	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437868	SCV000506504	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443826	SCV000506505	likely pathogenic	Adenoid cystic carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426992	SCV000506506	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436802	SCV000506507	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419553	SCV000506508	likely pathogenic	Myelodysplastic syndrome	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429404	SCV000506509	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436505	SCV000506510	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418395	SCV000506511	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429096	SCV000506512	likely pathogenic	Thyroid tumor	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438902	SCV000506513	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421701	SCV000506514	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428012	SCV000506515	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438707	SCV000506516	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424087	SCV000506517	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434677	SCV000506518	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445233	SCV000506519	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only