Submissions for variant NM_005343.4(HRAS):c.34G>T (p.Gly12Cys) (rs104894229)

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare 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	2016-08-31	criteria provided, single submitter	clinical testing	The G12C pathogenic variant in the HRAS gene has been reported previously to be associated with Costello syndrome, including one de novo observation (Kerr et al., 2006, Niihori et al., 2011; Lorenz et al., 2012). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G12C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, the glycine codons 12 and 13 of RAS proteins within the RAS/MAPK pathway are functionally important for GDP/GTP binding and are considered hot spots" for pathogenic variants (Wey et al. 2013; Gripp et al. 2012). Missense variants at the same (G12S/V/A/D) in nearby residues (G13C/D) have been reported in the Human Gene Mutation Database in association with Costello syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, functional studies of the G12C variant have shown that it results in increased active, GTP-bound HRAS (Niihori et al., 2011)."
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children	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; Epidermal nevus syndrome; Urinary bladder cancer; Costello syndrome; Epidermal nevus; Follicular thyroid carcinoma	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 Praxis fuer Humangenetik Tuebingen	RCV000212495	SCV001247463	pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	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.
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	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 Neoplasms	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	Adenocarcinoma of prostate	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	Neoplasm of the thyroid gland	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	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438707	SCV000506516	likely pathogenic	Uterine cervical neoplasms	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