Total submissions: 29
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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, |
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). |
Gene |
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. |
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. |
Molecular Diagnostics Lab, |
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, |
RCV000762847 | SCV000893207 | pathogenic | Large congenital melanocytic nevus; Epidermal nevus syndrome; Urinary bladder cancer; Costello syndrome; Epidermal nevus; Thyroid cancer, nonmedullary, 2 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
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. |
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 |
RCV000428812 | SCV000504407 | pathogenic | Neoplasm of the thyroid gland | 2014-10-02 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439954 | SCV000504408 | likely pathogenic | Neoplasm | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439052 | SCV000506576 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420958 | SCV000506577 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431688 | SCV000506578 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441514 | SCV000506579 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424247 | SCV000506580 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434069 | SCV000506581 | likely pathogenic | Chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445225 | SCV000506582 | likely pathogenic | Neoplasm of uterine cervix | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000433893 | SCV000506584 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445336 | SCV000506585 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426653 | SCV000506586 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436007 | SCV000506587 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444110 | SCV000506588 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425964 | SCV000506589 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436205 | SCV000506590 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417661 | SCV000506591 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Clinical Molecular Genetics Laboratory, |
RCV000678903 | SCV000805106 | pathogenic | Noonan syndrome | 2017-08-24 | no assertion criteria provided | clinical testing |