ClinVar Miner

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

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Total submissions: 48
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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 2019-12-11 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 RCV001283297 SCV000603969 pathogenic none 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
Integrated Genetics/Laboratory Corporation of America 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
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 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 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
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 (disease) 2020-09-01 no assertion criteria provided provider interpretation

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