ClinVar Miner

Submissions for variant NM_005343.4(HRAS):c.37G>T (p.Gly13Cys) (rs104894228)

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Total submissions: 29
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000149831 SCV000196675 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
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
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.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678903 SCV000805106 pathogenic Noonan syndrome 2017-08-24 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000428812 SCV000504407 pathogenic Neoplasm of the thyroid gland 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 Adenocarcinoma of stomach 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 Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434069 SCV000506581 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445225 SCV000506582 likely pathogenic Uterine cervical neoplasms 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
Fulgent Genetics,Fulgent Genetics RCV000762847 SCV000893207 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 RCV000207504 SCV000207847 pathogenic not provided 2018-05-04 criteria provided, single submitter clinical testing The G13C variant in the HRAS gene has been reported previously in multiple unrelated individuals with Costello syndrome and is one of the common HRAS variants associated with this disorder (Estep et al., 2006; Gripp et al., 2006; Gripp et al., 2011). In addition to the classic Costello features, this variant has been described in patients with unique ectodermal findings such as sparse hair in early childhood and long eyelashes, and appears to have a low incidence of papillomata (Gripp et al., 2011). The G13C 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. The G13C variant is a non-conservative amino acid substitution, which occurs at a conserved Glycine residue at codon 12; the majority of pathogenic variants in the HRAS gene (>90%) alter the conserved glycine residues at positions 12 and 13 (Aoki et al., 2005; Gripp et al., 2006). 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). Therefore, we interpret G13C as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000013440 SCV000259986 pathogenic Costello syndrome 2018-08-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 13 of the HRAS protein (p.Gly13Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases and has been reported in multiple individuals with Costello syndrome (PMID: 16372351, 21438134, 18042262, 16329078). ClinVar contains an entry for this variant (RCV000013440, RCV000149831). Experimental studies in vitro have found that this missense change constitutively activates RAS signaling and speeds up the cellular aging process, consistent with other well characterized deleterious mutations in this region of the HRAS protein (PMID: 21850009). This missense change is located in codon 13 of the HRAS gene product. Genetic studies of individuals with Costello syndrome show that more than 90% of all HRAS missense variants in these patients occur in either codon 12 or 13 of this gene (PMID: 16329078, 18042262, 21438134, 16372351). This indicates that missense changes involving these two codons are a common cause of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare 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).
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000207504 SCV000263057 pathogenic not provided 2014-06-04 criteria provided, single submitter clinical testing
OMIM RCV000013440 SCV000033687 pathogenic Costello syndrome 2011-04-01 no assertion criteria provided literature only

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