Submissions for variant NM_005343.4(HRAS):c.35G>C (p.Gly12Ala) (rs104894230)

Total submissions: 31

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000207503	SCV000207845	pathogenic	not provided	2018-12-19	criteria provided, single submitter	clinical testing	The G12A missense variant in the HRAS gene has been reported previously in association with disorders in the Noonan syndrome spectrum, including instances of apparent de novo inheritance (Aoki et al., 2005; Søvik et al., 2009). The variant 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. 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. Functional studies have shown that G12A results in increased phosphorylation of ERK, suggesting an activation of the RAS/MAPK pathway (Denayer et al., 2008; Niihori et al., 2011). Missense variants in the same codon (G12S/C/D/V) and in a nearby residue (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.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children	RCV000207503	SCV000263054	pathogenic	not provided	2014-06-04	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000013437	SCV000698555	pathogenic	Costello syndrome	2017-07-17	criteria provided, single submitter	clinical testing	Variant summary: The HRAS c.35G>C (p.Gly12Ala) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies showed that this variant increased RAS pathway activation in NIH 3T3 cells (Niihori_JHG_2011) and increased proliferation in Ba/F3 cells (Denayer_HM_2008). The variant of interest has not been found in a large, broad control population, ExAC in 120014 control chromosomes. This variant was reported in multiple Costello syndrome patients, including de novo occurrences (Aoki_NatGen_2005, Robbins_AJMG_2016, Niihori_JHG_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics	RCV000623953	SCV000741342	pathogenic	Inborn genetic diseases	2016-03-03	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Fulgent Genetics,Fulgent Genetics	RCV000762848	SCV000893208	pathogenic	Congenital giant melanocytic nevus; Epidermal nevus syndrome; Bladder cancer, somatic; Costello syndrome; Epidermal nevus; Follicular thyroid carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000013437	SCV000956118	pathogenic	Costello syndrome	2018-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with alanine at codon 12 of the HRAS protein (p.Gly12Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with Costello syndrome and is a frequent pathogenic variant in the HRAS gene (PMID: 28027064, 22420426, 21850009, 18042262, 17601930, 16835863, 16443854, 16372351, 16170316). It has been reported to arise de novo in many of these individuals. ClinVar contains an entry for this variant (Variation ID: 12603). Experimental studies in transfected cell lines have shown that this missense change causes increased downstream RAS pathway activation (PMID: 21850009, 17979197, 24224811). This variant disrupts the p.Gly12 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000013437	SCV000033684	pathogenic	Costello syndrome	2005-10-01	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423741	SCV000506520	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433587	SCV000506521	likely pathogenic	Adenocarcinoma of prostate	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445257	SCV000506522	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426130	SCV000506523	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436832	SCV000506524	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444092	SCV000506525	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425989	SCV000506526	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435805	SCV000506527	likely pathogenic	Neoplasm of the breast	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418547	SCV000506528	likely pathogenic	Adenoid cystic carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428375	SCV000506529	likely pathogenic	Nasopharyngeal Neoplasms	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435619	SCV000506530	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417508	SCV000506531	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428172	SCV000506532	likely pathogenic	Neoplasm of the thyroid gland	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441501	SCV000506533	likely pathogenic	Uterine cervical neoplasms	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423622	SCV000506534	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430806	SCV000506535	likely pathogenic	Papillary renal cell carcinoma, sporadic	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440663	SCV000506536	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423413	SCV000506537	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433266	SCV000506538	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442448	SCV000506539	likely pathogenic	Myelodysplastic syndrome	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422263	SCV000506540	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432956	SCV000506541	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445090	SCV000506542	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425511	SCV000506543	likely pathogenic	Uterine Carcinosarcoma	2016-05-31	no assertion criteria provided	literature only