ClinVar Miner

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

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Total submissions: 31
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
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
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
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.
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.
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.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000207503 SCV000263054 pathogenic not provided 2014-06-04 criteria provided, single submitter clinical testing
OMIM RCV000013437 SCV000033684 pathogenic Costello syndrome 2005-10-01 no assertion criteria provided literature only

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