Total submissions: 36
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000013447 | SCV000062132 | pathogenic | Costello syndrome | 2012-11-20 | criteria provided, single submitter | clinical testing | The Gly12Cys variant in HRAS has been reported in the literature in six individu als with severe neonatal Costello syndrome (Kerr 2006, Lo 2008, Lin 2009, Niihor i 2011, Lorenz 2012). This variant has been reported to have occurred de novo in one proband (Lorenz 2012). Several other DNA variants affecting codon 12 of HRA S are commonly observed in patients with Costello syndrome (Niihori 2011). There fore, this variant is highly likely to be pathogenic. |
Gene |
RCV000212495 | SCV000207843 | pathogenic | not provided | 2016-08-31 | criteria provided, single submitter | clinical testing | The G12C pathogenic variant in the HRAS gene has been reported previously to be associated with Costello syndrome, including one de novo observation (Kerr et al., 2006, Niihori et al., 2011; Lorenz et al., 2012). It 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. G12C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. 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. Moreover, the glycine codons 12 and 13 of RAS proteins within the RAS/MAPK pathway are functionally important for GDP/GTP binding and are considered hot spots" for pathogenic variants (Wey et al. 2013; Gripp et al. 2012). Missense variants at the same (G12S/V/A/D) in nearby residues (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. Additionally, functional studies of the G12C variant have shown that it results in increased active, GTP-bound HRAS (Niihori et al., 2011)." |
Molecular Diagnostics Lab, |
RCV000013447 | SCV000263053 | pathogenic | Costello syndrome | 2014-06-04 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000762849 | SCV000893209 | pathogenic | Large congenital melanocytic nevus; Epidermal nevus syndrome; Urinary bladder cancer; Costello syndrome; Epidermal nevus; Follicular thyroid carcinoma | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Blueprint Genetics | RCV000212495 | SCV000927854 | pathogenic | not provided | 2018-08-14 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000212495 | SCV001247463 | pathogenic | not provided | 2016-11-01 | criteria provided, single submitter | clinical testing | |
Integrated Genetics/Laboratory Corporation of America | RCV000013447 | SCV001448594 | pathogenic | Costello syndrome | 2020-11-09 | criteria provided, single submitter | clinical testing | Variant summary: HRAS c.34G>T (p.Gly12Cys) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) 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 250294 control chromosomes (gnomAD). c.34G>T has been reported in the literature in multiple individuals affected with Costello Syndrome (e.g. Niihori_2011, McCormick_2013, Choi_2019). These data indicate that the variant is very likely to be associated with disease. In functional studies, Niihori et al (Niihori_2011) report that there was an increase in guanosine triphosphate (GTP)-bound HRAS and activation of RAS signaling pathway (as measured by the activation of ELK1 and c-Jun) in cells transfected with the variant of interest. In addition, HGMD database reports several other missense variants affecting the same codon and nearby codons (e.g. p.G12R, p.G12S, p.G12V, p.G12A, p.G13D, p.G13C) suggesting this area might be a mutational hotspot. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
OMIM | RCV000013447 | SCV000033694 | pathogenic | Costello syndrome | 2012-06-10 | no assertion criteria provided | literature only | |
OMIM | RCV000029211 | SCV000051857 | pathogenic | Nevus sebaceous | 2012-06-10 | no assertion criteria provided | literature only | |
OMIM | RCV000032851 | SCV000056620 | pathogenic | Epidermal nevus | 2012-06-10 | no assertion criteria provided | literature only | |
Baylor Genetics | RCV000149829 | SCV000196673 | pathogenic | Rasopathy | no assertion criteria provided | clinical testing | Variant classified using ACMG guidelines | |
Database of Curated Mutations |
RCV000440052 | SCV000505663 | likely pathogenic | Bladder carcinoma | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439243 | SCV000506496 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422023 | SCV000506497 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431815 | SCV000506498 | likely pathogenic | Nasopharyngeal Neoplasms | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444512 | SCV000506499 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424380 | SCV000506500 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431602 | SCV000506501 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443678 | SCV000506502 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427213 | SCV000506503 | likely pathogenic | Papillary renal cell carcinoma, sporadic | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437868 | SCV000506504 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443826 | SCV000506505 | likely pathogenic | Adenoid cystic carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426992 | SCV000506506 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436802 | SCV000506507 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419553 | SCV000506508 | likely pathogenic | Myelodysplastic syndrome | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429404 | SCV000506509 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436505 | SCV000506510 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418395 | SCV000506511 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429096 | SCV000506512 | likely pathogenic | Neoplasm of the thyroid gland | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438902 | SCV000506513 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421701 | SCV000506514 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428012 | SCV000506515 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438707 | SCV000506516 | likely pathogenic | Uterine cervical neoplasms | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424087 | SCV000506517 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434677 | SCV000506518 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445233 | SCV000506519 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only |