Total submissions: 23
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000157914 | SCV000207849 | pathogenic | not provided | 2017-03-22 | criteria provided, single submitter | clinical testing | The G13V missense change in the HRAS gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. Nevertheless, the vast majority of pathogenic HRAS germline mutations association with Costello syndrome alter the conserved glycine residues at positions 12 and 13, including the mutations G13D and G13C (Aoki et al., 2005; Estep et al., 2006; Gripp et al., 2006). Furthermore, 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. Additionally, G13V is not observed in large population cohorts (Lek et al., 2016). |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000590121 | SCV000698559 | pathogenic | Costello syndrome | 2023-03-27 | criteria provided, single submitter | clinical testing | Variant summary: HRAS c.38G>T (p.Gly13Val) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250330 control chromosomes (gnomAD). c.38G>T has been reported in the literature in settings of WES in at least two fetuses affected with multiple congenital abnormalities, including one case where it was confirmed to be de novo, although it is not clear whether these individuals would have met the clinical criteria for Costello or Noonan syndromes, these findings suggest the variant may be associated with disease (e.g. Lefebvre_2021, Gabriel_2022). The variant of interest has also been reported in numerous publications as a somatic mutation found in various types of cancers. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant is associated with an increased rate of guanine nucleotide exchange compared to the WT protein (Wey_2013). Additionally, Glycine 13 is one of the two most mutated amino acids in Costello Syndrome, and several other variants located at codon 13 have been associated with Costello Syndrome (G13C, G13D, G13S; Wey_2013). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Equipe Genetique des Anomalies du Developpement, |
RCV000590121 | SCV001994823 | pathogenic | Costello syndrome | 2021-10-28 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000157914 | SCV004563410 | pathogenic | not provided | 2023-09-30 | criteria provided, single submitter | clinical testing | The HRAS c.38G>T; p.Gly13Val variant (rs104894226) is reported in the literature in multiple individuals affected with Costello syndrome and Schimmelpenning-Feuerstein-Mims syndrome (Gabriel 2022, Gripp 2011, Lefebvre 2021, Luo 2021). This variant is also reported in ClinVar (Variation ID: 180848) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Asp, Arg, Cys) have been reported in individuals with RASopathies and are considered pathogenic (Gripp 2011, Lefebvre 2021, Luo 2021). Computational analyses predict that this variant is deleterious (REVEL: 0.791). Based on available information, this variant is considered to be pathogenic. References: Gabriel H et al. Trio exome sequencing is highly relevant in prenatal diagnostics. Prenat Diagn. 2022 Jun;42(7):845-851. PMID: 34958143. Gripp KW et al. Phenotypic analysis of individuals with Costello syndrome due to HRAS p.G13C. Am J Med Genet A. 2011 Apr;155A(4):706-16. PMID: 21438134. Lefebvre M et al. Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations. J Med Genet. 2021 Jun;58(6):400-413. PMID: 32732226. Luo Q et al. Expanding mutational spectrum of HRAS by a patient with Schimmelpenning-Feuerstein-Mims syndrome. J Dermatol. 2021 Aug;48(8):1273-1276. PMID: 34109654. |
Database of Curated Mutations |
RCV000442670 | SCV000504833 | likely pathogenic | Thymoma | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421468 | SCV000506560 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432148 | SCV000506561 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444507 | SCV000506562 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424767 | SCV000506563 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434580 | SCV000506564 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444587 | SCV000506565 | likely pathogenic | Neoplasm of uterine cervix | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427265 | SCV000506566 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437080 | SCV000506567 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419846 | SCV000506568 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426169 | SCV000506569 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436822 | SCV000506570 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418712 | SCV000506571 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429433 | SCV000506572 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439230 | SCV000506573 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418565 | SCV000506574 | likely pathogenic | B-cell chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428389 | SCV000506575 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Institute of Medical Sciences, |
RCV001255688 | SCV001432253 | pathogenic | Lip and oral cavity carcinoma | 2019-04-30 | no assertion criteria provided | research | |
Yale Center for Mendelian Genomics, |
RCV001849323 | SCV002106425 | pathogenic | KA-like vemurafenib-induced squamous lesions | 2016-06-07 | no assertion criteria provided | literature only |