Submissions for variant NM_005343.4(HRAS):c.38G>T (p.Gly13Val)

dbSNP: rs104894226

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	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, LabCorp	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, Université de Bourgogne	RCV000590121	SCV001994823	pathogenic	Costello syndrome	2021-10-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, 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 (DoCM)	RCV000442670	SCV000504833	likely pathogenic	Thymoma	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421468	SCV000506560	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432148	SCV000506561	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444507	SCV000506562	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424767	SCV000506563	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434580	SCV000506564	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444587	SCV000506565	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427265	SCV000506566	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437080	SCV000506567	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419846	SCV000506568	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426169	SCV000506569	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	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 (DoCM)	RCV000418712	SCV000506571	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429433	SCV000506572	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439230	SCV000506573	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418565	SCV000506574	likely pathogenic	B-cell chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428389	SCV000506575	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Institute of Medical Sciences, Banaras Hindu University	RCV001255688	SCV001432253	pathogenic	Lip and oral cavity carcinoma	2019-04-30	no assertion criteria provided	research
Yale Center for Mendelian Genomics, Yale University	RCV001849323	SCV002106425	pathogenic	KA-like vemurafenib-induced squamous lesions	2016-06-07	no assertion criteria provided	literature only