ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.37G>T (p.Gly13Cys)

dbSNP: rs104894228
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Total submissions: 32
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000678903 SCV000616363 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.37G>T (p.Gly13Cys) 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 21438134, 16329078). The p.Gly13Cys variant has been identified in at least 3 other independent occurrence in patients with clinical features of a RASopathy (PS4_Moderate; PMID: 16372351). 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). Computational prediction tools and conservation analysis suggest that the p.Gly13Cys 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). 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): PP2, PP3, PM1, PM2, PS4_Moderate, PS2_VeryStrong.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000013440 SCV000062140 pathogenic Costello syndrome 2010-06-29 criteria provided, single submitter clinical testing The Gly13Cys variant has previously been associated with the clinical features o f Costello syndrome (Estep 2006, Gripp 2006, Kratz 2007). This variant has been shown to have occurred de novo in at least one individual. In summary, this vari ant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org /LMM).
GeneDx RCV000207504 SCV000207847 pathogenic not provided 2022-06-21 criteria provided, single submitter clinical testing Functional studies demonstrate that G13C alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which upregulates the Ras/MAPK pathway (Wey et al., 2013); The majority of missense variants in this gene are considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23093928, 16372351, 24803665, 24224811, 16329078, 21438134, 19213030, 28337834, 28973083, 28371260, 16835863, 33240318, 33482860, 29493581)
Invitae RCV000013440 SCV000259986 pathogenic Costello syndrome 2021-08-12 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000207504 SCV000263057 pathogenic not provided 2014-06-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV000013440 SCV000807270 pathogenic Costello syndrome 2017-09-01 criteria provided, single submitter clinical testing This same amino acid substitution has been previously reported as disease-causing and was found once in our laboratory de novo in a newborn female with prematurity, non-immune fetal hydrops, mild microcytic anemia, 2 muscular apical VSDs, large PDA and PFO, cup-shaped ears, hypotonia
Fulgent Genetics,Fulgent Genetics RCV000762847 SCV000893207 pathogenic Large congenital melanocytic nevus; Linear nevus sebaceous syndrome; Malignant tumor of urinary bladder; Costello syndrome; Epidermal nevus; Thyroid cancer, nonmedullary, 2 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000149831 SCV000917529 pathogenic RASopathy 2018-09-24 criteria provided, single submitter clinical testing Variant summary: HRAS c.37G>T (p.Gly13Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276492 control chromosomes (gnomAD). c.37G>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions and occurs at a codon that is known to be associated with disease (McCormick_2013, Gripp_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome Diagnostics Laboratory,The Hospital for Sick Children RCV001813188 SCV002060965 pathogenic Noonan syndrome and Noonan-related syndrome 2018-06-01 criteria provided, single submitter clinical testing
OMIM RCV000013440 SCV000033687 pathogenic Costello syndrome 2011-04-01 no assertion criteria provided literature only
Baylor Genetics RCV000149831 SCV000196675 pathogenic RASopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Database of Curated Mutations (DoCM) RCV000428812 SCV000504407 pathogenic Thyroid tumor 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439954 SCV000504408 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439052 SCV000506576 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420958 SCV000506577 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431688 SCV000506578 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441514 SCV000506579 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424247 SCV000506580 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434069 SCV000506581 likely pathogenic B-cell chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445225 SCV000506582 likely pathogenic Neoplasm of uterine cervix 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423190 SCV000506583 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433893 SCV000506584 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445336 SCV000506585 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426653 SCV000506586 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436007 SCV000506587 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444110 SCV000506588 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425964 SCV000506589 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436205 SCV000506590 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417661 SCV000506591 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678903 SCV000805106 pathogenic Noonan syndrome 2017-08-24 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000207504 SCV001799200 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000207504 SCV001955013 pathogenic not provided no assertion criteria provided clinical testing

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