Total submissions: 61
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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, |
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). |
Gene |
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 |
RCV000081295 | SCV000227361 | pathogenic | not provided | 2015-08-27 | criteria provided, single submitter | clinical testing | |
Molecular Diagnostics Lab, |
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, |
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, |
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, |
RCV000013435 | SCV000781527 | pathogenic | Costello syndrome | 2016-11-01 | criteria provided, single submitter | clinical testing | |
Rady Children's Institute for Genomic Medicine, |
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, |
RCV000013435 | SCV001167662 | pathogenic | Costello syndrome | 2019-01-11 | criteria provided, single submitter | clinical testing | |
Women's Health and 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 |
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, |
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 - |
RCV000013435 | SCV002059320 | pathogenic | Costello syndrome | 2018-03-01 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV001813185 | SCV002060955 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2016-12-19 | criteria provided, single submitter | clinical testing | |
Greenwood Genetic Center Diagnostic Laboratories, |
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 |
RCV000430725 | SCV000506472 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440993 | SCV000506473 | likely pathogenic | Adenoid cystic carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423310 | SCV000506474 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433576 | SCV000506475 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440297 | SCV000506476 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422656 | SCV000506477 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432984 | SCV000506478 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445039 | SCV000506479 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425542 | SCV000506480 | likely pathogenic | Thyroid tumor | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432342 | SCV000506481 | likely pathogenic | Papillary renal cell carcinoma, sporadic | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443940 | SCV000506482 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000435163 | SCV000506484 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417494 | SCV000506485 | likely pathogenic | Uterine carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427772 | SCV000506486 | likely pathogenic | Prostate adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438022 | SCV000506487 | likely pathogenic | Neoplasm of uterine cervix | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420366 | SCV000506488 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430608 | SCV000506489 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440863 | SCV000506490 | likely pathogenic | Myelodysplastic syndrome | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419709 | SCV000506491 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430011 | SCV000506492 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440237 | SCV000506493 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422253 | SCV000506494 | likely pathogenic | Nasopharyngeal neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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, |
RCV000013435 | SCV000805105 | pathogenic | Costello syndrome | 2017-12-18 | no assertion criteria provided | clinical testing | |
Institute of Medical Sciences, |
RCV001255689 | SCV001432254 | pathogenic | Lip and oral cavity carcinoma | 2019-04-30 | no assertion criteria provided | research | |
Human Genome Sequencing Center Clinical Lab, |
RCV001257537 | SCV001434363 | pathogenic | Rhabdomyosarcoma | 2020-09-01 | no assertion criteria provided | provider interpretation | |
Genome Diagnostics Laboratory, |
RCV000081295 | SCV001809092 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000081295 | SCV001955792 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000081295 | SCV001967870 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Perkin |
RCV000013435 | SCV002025029 | pathogenic | Costello syndrome | 2019-10-29 | no assertion criteria provided | clinical testing |