ClinVar Miner

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

dbSNP: rs104894226
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Total submissions: 24
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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.
Clinical Genomics Laboratory, Washington University in St. Louis RCV004562310 SCV005049536 likely pathogenic Large congenital melanocytic nevus 2024-01-15 criteria provided, single submitter clinical testing The HRAS c.38G>T (p.Gly13Val) variant was identified at an allelic fraction consistent with somatic origin. This variant has been identified in an individual with Schimmelpenning-Feuerstein-Mims (SFM) syndrome (Luo Q et al., PMID: 34109654). This variant has been reported in the ClinVar database as pathogenic or likely pathogenic in both somatic and germline states (ClinVar Variation ID: 180848). It has also been reported as a somatic variant in multiple cases in the Catalogue of Somatic Mutations in Cancer (COSMIC, Genomic Mutation ID: COSV54237051). This variant is absent from the general population (gnomAD v4.0.0), indicating that it is not a common variant. Two other variants in the same codon, c.38G>A (p.Gly13Asp) and c.37G>T (p.Gly13Cys), have been reported and are considered pathogenic (ClinVar Variation IDs: 12604 and 12606). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to HRAS function. In support of this prediction, functional studies show that the HRAS c.38G>T (p.Gly13Val) variant causes a higher cellular proportion of the biologically active form of HRAS (Wey M et al., PMID: 24224811). Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the HRAS c.38G>T (p.Gly13Val) variant is classified as likely pathogenic.
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

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