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

dbSNP: rs104894229

Total submissions: 61

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, Mass General Brigham 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	2019-11-29	criteria provided, single submitter	clinical testing	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); Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Classified as pathogenic by the ClinGen RASopathy Expert Panel (SCV000616364.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 22317973, 27195699, 21850009, 24224811, 23093928, 16329078, 16170316, 19371735, 23751039, 21834037, 20979192, 27705751, 26350204, 24803665, 27589201, 25722179, 24169525, 28141901, 28027064, 16835863, 17412879, 16881968, 19669404, 30138938, 30055033, 30792901, 30050098, 25815234, 31394527, 29907801, 31560489, 31564432, 31712860, 31965297, 31795565, 32369273, 32371413, 33482860, 32681669)
Eurofins NTD LLC (GA)	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	2021-08-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000081295	SCV000603969	pathogenic	not provided	2020-02-16	criteria provided, single submitter	clinical testing	The HRAS c.34G>A; p.Gly12Ser variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011, Zampino 2007). 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) and tumor samples (Aoki 2005, Estep 2006). Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. Based on available information, this variant is considered to be pathogenic. References: Aoki Y et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005; 37(10):1038-40. Estep A et al. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A. 2006; 140(1):8-16. Gripp K et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006; 140(1):1-7. Kerr B et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006; 43(5):401-5. 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; 56(10):707-15. Zampino G et al. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat. 2007; 28(3):265-72.
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,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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000013435	SCV001362310	pathogenic	Costello syndrome	2019-05-13	criteria provided, single submitter	clinical testing	Variant summary: HRAS c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250394 control chromosomes (gnomAD). The variant, c.34G>A, has been reported in the literature in multiple individuals affected with Costello Syndrome (Aoki_2005, Kerr_2006, Gripp_2006, Niihori_2011). These data indicate that the variant is very likely to be associated with disease. At least two publication report experimental evidence evaluating an impact on protein function (Gain of function) and the effect of this variant is similar to other HRAS pathogenic variants (Paquin_2009, Niihori_2011). Eight ClinVar submissions from clinical diagnostic laboratories and one expert panel (ClinGen RASopathy) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV000013435	SCV001423659	pathogenic	Costello syndrome	2018-04-06	criteria provided, single submitter	clinical testing	[ACMG/AMP: PS2, PM1, PM2, PM5, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Ambry Genetics	RCV001267097	SCV001445278	pathogenic	Inborn genetic diseases	2018-03-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000013435	SCV001520829	pathogenic	Costello syndrome	2020-10-21	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000013435	SCV001976682	pathogenic	Costello syndrome	2021-10-01	criteria provided, single submitter	clinical testing	PS1, PM1, PM2, PM5, PP2, PP3, PP5
3billion	RCV000013435	SCV002058657	pathogenic	Costello syndrome	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 16835863, 20660566, 19206176, 16329078, 16969868, 19371735, 18039947, 16372351, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17412879, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.695, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Costello syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012600, VCV000012603, VCV000012612, VCV000012613, VCV000040430, VCV000163690, VCV000180854, VCV000279921, VCV001209208, PM5_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012602, PS1_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centogene AG - the Rare Disease Company	RCV000013435	SCV002059320	pathogenic	Costello syndrome	2018-03-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813185	SCV002060955	pathogenic	Noonan syndrome and Noonan-related syndrome	2016-12-19	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center	RCV000013435	SCV002568185	pathogenic	Costello syndrome	2022-06-07	criteria provided, single submitter	clinical testing	PS2 PS3 PS4 PM2 PM5
MGZ Medical Genetics Center	RCV000013435	SCV002580200	pathogenic	Costello syndrome	2021-09-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453256	SCV002615093	pathogenic	Cardiovascular phenotype	2022-04-15	criteria provided, single submitter	clinical testing	The p.G12S pathogenic mutation (also known as c.34G>A), located in coding exon 1 of the HRAS gene, results from a G to A substitution at nucleotide position 34. The glycine at codon 12 is replaced by serine, an amino acid with similar properties. This alteration has been reported in numerous individuals with a clinical diagnosis of Costello syndrome with the majority of these cases occurring de novo (Aoki Y et al. Nat Genet, 2005 Oct;37:1038-40; Gripp KW et al. Am J Med Genet A, 2006 Jan;140:1-7; Kerr B et al. J Med Genet, 2006 May;43:401-5; Estep AL et al. Am J Med Genet A, 2006 Jan;140:8-16; Zampino G et al. Hum Mutat, 2007 Mar;28:265-72; Sol-Church K et al. Am J Med Genet A, 2009 Mar;149A:315-21; Sriboonnark L et al. Case Rep Pediatr, 2015 Feb;2015:934865; Leoni C et al. J Pediatr, 2016 Mar;170:322-4; Huang Z et al. Cell Physiol Biochem, 2018 Aug;49:295-305; Levin MD et al. Am J Med Genet A, 2018 08;176:1711-1722; Kingsmore SF et al. Am J Hum Genet, 2019 10;105:719-733; Chinton J et al. Arch Argent Pediatr, 2019 10;117:330-337; Miller CR et al. Cold Spring Harb Mol Case Stud, 2020 06;6:[ePub ahead of print]). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Athena Diagnostics Inc	RCV000081295	SCV002817295	pathogenic	not provided	2021-03-10	criteria provided, single submitter	clinical testing	Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID 28139825). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in approximately 80% of individuals with Costello syndrome and is reported to be the most frequent pathogenic variant in the HRAS gene (PMID: 21834037, 20979192, 17054105, 16881968, 16372351, 16170316, 16329078, 16443854). This variant occurs de novo in an individual tested at Athena Diagnostics and in previously reported individuals with clinical features of Costello syndrome (PMID: 16170316, 16372351, 16881968, 17054105, 21834037, 28027064). Germline mosaicism has been reported as an inheritance mechanism for multiple cases, with the majority arising in the paternal germline (PMID: 24259709, 16835863, 21834037).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
OMIM	RCV000013435	SCV000033682	pathogenic	Costello syndrome	2014-04-01	no assertion criteria provided	literature only
OMIM	RCV000013436	SCV000033683	pathogenic	Congenital myopathy 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	Gastric adenocarcinoma	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	Thyroid tumor	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	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438022	SCV000506487	likely pathogenic	Neoplasm of uterine cervix	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	Breast neoplasm	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 neoplasm	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	Woolly hair nevus	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
Institute of Medical Sciences, Banaras Hindu University	RCV001255689	SCV001432254	pathogenic	Lip and oral cavity carcinoma	2019-04-30	no assertion criteria provided	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257537	SCV001434363	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000081295	SCV001809092	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000081295	SCV001955792	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000081295	SCV001967870	pathogenic	not provided		no assertion criteria provided	clinical testing
PerkinElmer Genomics	RCV000013435	SCV002025029	pathogenic	Costello syndrome	2019-10-29	no assertion criteria provided	clinical testing