Submissions for variant NM_005343.4(HRAS):c.34G>A (p.Gly12Ser) (rs104894229)

Total submissions: 43

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000013435	SCV000616364	pathogenic	Costello syndrome	2017-04-03	reviewed by expert panel	curation	The c.34G>A (p.Gly12Ser) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 16170316, 16835863, 16443854, 16835863, 16881968, 17054105, 19669404). The p.Gly12Ser variant has been identified in >5 independent occurrences in patients with clinical features of a RASopathy (PS4; PMID: 20660566, 16372351, 16329078, 16969868, 18039947, 19371735, 19206176, 16835863). In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3; PMID: 17412879). Computational prediction tools and conservation analysis suggest that the p.Gly12Ser variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS 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; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PS3, PM1, PM2, PP2, PP3.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000013435	SCV000062131	pathogenic	Costello syndrome	2012-07-30	criteria provided, single submitter	clinical testing	The Gly12Ser variant in HRAS is the most common variant associated with Costello syndrome (Aoki 2005, Kerr 2006, Gripp 2006, Gori 2008, Dileone 2010, Estep 2006 , Gripp 2006, Lo 2008, Paquin 2009, Sol-Church 2009, Sol-Church 2006, van der Bu rgt 2007, van Steensel 2006, Zampino 2007, Zhang 2009). This variant has been re ported to have occurred de novo in many individuals. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
GeneDx	RCV000081295	SCV000207842	pathogenic	not provided	2018-05-18	criteria provided, single submitter	clinical testing	The G12S missense pathogenic variant in the HRAS gene is one of the common variants associated with Costello syndrome, of which greater than 90% alter the conserved glycine residues at positions 12 and 13 (Aoki et al., 2005; Gripp et al., 2006). Functional studies indicate that the G12S variant alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which up-regulates the Ras/MAPK pathway (Wey et al. 2013). The G12S variant is not observed in large population cohorts (Lek et al., 2016). G12S has been observed multiple times de novo and other missense variants in the same residue (G12C, G12D, G12V, G12A) and in a nearby residue (G13C, G13D) have also been reported in the Human Gene Mutation Database in association with disorders in the Noonan syndrome spectrum (Stenson et al., 2014). We interpret G12S as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000081295	SCV000227361	pathogenic	not provided	2015-08-27	criteria provided, single submitter	clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children	RCV000013435	SCV000263052	pathogenic	Costello syndrome	2014-06-04	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000013435	SCV000263952	pathogenic	Costello syndrome	2015-04-01	criteria provided, single submitter	clinical testing
Invitae	RCV000013435	SCV000288856	pathogenic	Costello syndrome	2019-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with serine at codon 12 of the HRAS protein (p.Gly12Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (rs104894229, ExAC no frequency). This variant has been reported in many individuals affected with Costello syndrome, and is considered one of the most frequent pathogenic variants in the HRAS gene (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). It has been reported to arise de novo in many of these individuals. ClinVar contains an entry for this variant (Variation ID: 12602). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000081295	SCV000603969	pathogenic	not provided	2017-08-08	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute	RCV000013435	SCV000680007	pathogenic	Costello syndrome	2016-12-16	criteria provided, single submitter	clinical testing	A heterozygous variant was identified in the HRAS gene, NM_176795.3(HRAS):c.34G>A and (chr11:534289). This substitution variant is predicted to create a change of a glycine to a serine at amino acid position 12, NP_001123914.1(HRAS):p.(Gly12Ser). The glycine at this position has high conservation but it is not situated in a known functional domain. In silico software predicts this variant to be disease causing. This variant has not been previously observed in our patient cohort and is not present in population databases. It has previously been observed in multiple families with Costello syndrome (Aoki et al 2005 Nat Genet, Kerr et al 2006 J Med Genet, Soi-Church et al Hum Mutat 2006 and Zampino et al 2007 Hum Mutat) and it has been classified as a common pathogenic variant. Based on current information this variant has been classified as PATHOGENIC.
Center for Human Genetics, Inc	RCV000013435	SCV000781527	pathogenic	Costello syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000013435	SCV000996166	pathogenic	Costello syndrome	2018-07-03	criteria provided, single submitter	clinical testing	This established pathogenic variant is found in approximately 80% of individuals with Costello syndrome (PMID: 16170316, 22261753, 20301680). This variant has been classified in ClinVar as pathogenic by the ClinGen Rasopathy Expert Panel and by several clinical diagnostic laboratories (variant ID: 12602). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.34G>A (p.Gly12Ser) variant is classified as pathogenic.
Genomic Medicine Lab, University of California San Francisco	RCV000013435	SCV001167662	pathogenic	Costello syndrome	2019-01-11	criteria provided, single submitter	clinical testing
OMIM	RCV000013435	SCV000033682	pathogenic	Costello syndrome	2014-04-01	no assertion criteria provided	literature only
OMIM	RCV000013436	SCV000033683	pathogenic	Myopathy, congenital, with excess of muscle spindles	2014-04-01	no assertion criteria provided	literature only
OMIM	RCV000022796	SCV000044085	pathogenic	Epidermal nevus with urothelial cancer, somatic	2014-04-01	no assertion criteria provided	literature only
OMIM	RCV000029209	SCV000051855	pathogenic	Nevus sebaceous	2014-04-01	no assertion criteria provided	literature only
Baylor Genetics	RCV000149828	SCV000196672	pathogenic	Rasopathy		no assertion criteria provided	clinical testing	Variant classified using ACMG guidelines
Database of Curated Mutations (DoCM)	RCV000430725	SCV000506472	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440993	SCV000506473	likely pathogenic	Adenoid cystic carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423310	SCV000506474	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433576	SCV000506475	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440297	SCV000506476	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422656	SCV000506477	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432984	SCV000506478	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445039	SCV000506479	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425542	SCV000506480	likely pathogenic	Neoplasm of the thyroid gland	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432342	SCV000506481	likely pathogenic	Papillary renal cell carcinoma, sporadic	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443940	SCV000506482	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424896	SCV000506483	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435163	SCV000506484	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417494	SCV000506485	likely pathogenic	Uterine Carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427772	SCV000506486	likely pathogenic	Adenocarcinoma of prostate	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438022	SCV000506487	likely pathogenic	Uterine cervical neoplasms	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420366	SCV000506488	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430608	SCV000506489	likely pathogenic	Neoplasm of the breast	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440863	SCV000506490	likely pathogenic	Myelodysplastic syndrome	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419709	SCV000506491	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430011	SCV000506492	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440237	SCV000506493	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422253	SCV000506494	likely pathogenic	Nasopharyngeal Neoplasms	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432945	SCV000506495	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
OMIM	RCV000487471	SCV000574678	pathogenic	Nevus, woolly hair	2014-04-01	no assertion criteria provided	literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital	RCV000013435	SCV000805105	pathogenic	Costello syndrome	2017-12-18	no assertion criteria provided	clinical testing