Total submissions: 31
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genomic Medicine Lab, |
RCV001376004 | SCV001573009 | pathogenic | Non-immune hydrops fetalis | 2019-05-29 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV001781319 | SCV002016631 | likely pathogenic | Costello syndrome | 2019-12-18 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV001813211 | SCV002060964 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2021-05-08 | criteria provided, single submitter | clinical testing | |
Genesolutions, |
RCV001781319 | SCV003934962 | pathogenic | Costello syndrome | 2022-06-22 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001781319 | SCV004039160 | pathogenic | Costello syndrome | 2023-08-14 | criteria provided, single submitter | clinical testing | Variant summary: HRAS c.37G>C (p.Gly13Arg) 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.37G>C has been reported in numerous publications as a somatic mutation found in various types of cancers and at least one de novo case who may have Costello Syndrome (Sparks_2020). These data indicate that the variant is likely to be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function and functional analysis of HRAS c.37G>C confirmed constitutive activation of the MAPK and PI3KK-Akt signaling pathways (Spoerner_2010, Groesser_2012, Lopes-Ventura_2018). In addition, 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 (G13D, G13V, G13C; PMID: 24224811) in HGMD and classified as DV in our lab. The following publications have been ascertained in the context of this evaluation (PMID: 20937837, 22683711, 30191474, 33027564). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. |
Clinical Genomics Laboratory, |
RCV003458340 | SCV004176935 | pathogenic | Epidermolytic nevus | 2023-10-16 | criteria provided, single submitter | clinical testing | The HRAS c.37G>C (p.Gly13Arg) variant was identified at an allelic fraction likely supporting somatic origin. This variant has been reported in multiple individuals with epidermal nevus and nevus spilus (Farschtschi S et al., PMID: 25928347; Lim YH et al., PMID: 24006476; Hafner C et al., PMID: 22499344; Bender RP et al., PMID: 23599145; Sarin KY et al., PMID: 24390138; Sarin KY et al., PMID: 23884457). This variant has been reported in the ClinVar database as a pathogenic/likely pathogenic variant by multiple submitters (ClinVar ID: 35554) and in multiple cancer cases as a somatic variant in the cancer database COSMIC (Cosmic ID: COSV54236651). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. The HRAS c.37G>C (p.Gly13Arg) variant resides within a GTP binding domain of HRAS that is defined as a critical functional domain (Wey M et al., PMID: 24224811). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on HRAS function and in support of this prediction, functional studies show that this variant results in activation of the Ras-Raf-MAPK and PI3K-Akt signaling pathways and increased cellular proliferation (Groesser L et al., PMID: 22683711). The HRAS gene is defined by ClinGen's RASopathy expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Gelb BD et al., PMID: 29493581). Based on the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the HRAS c.37G>C (p.Gly13Arg) variant is classified as pathogenic. |
OMIM | RCV000029212 | SCV000051858 | pathogenic | Nevus sebaceous | 2014-06-01 | no assertion criteria provided | literature only | |
OMIM | RCV000029213 | SCV000051859 | pathogenic | Linear nevus sebaceous syndrome | 2014-06-01 | no assertion criteria provided | literature only | |
OMIM | RCV000032852 | SCV000056621 | pathogenic | Epidermal nevus | 2014-06-01 | no assertion criteria provided | literature only | |
OMIM | RCV000173005 | SCV000224024 | pathogenic | NEVUS SPILUS, SOMATIC | 2014-06-01 | no assertion criteria provided | literature only | |
OMIM | RCV000173006 | SCV000224025 | pathogenic | SPITZ NEVUS, SOMATIC | 2014-06-01 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418725 | SCV000504409 | pathogenic | Thyroid tumor | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431824 | SCV000506544 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000443949 | SCV000506545 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424371 | SCV000506546 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435072 | SCV000506547 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420481 | SCV000506548 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427669 | SCV000506549 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437649 | SCV000506550 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420422 | SCV000506551 | likely pathogenic | B-cell chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430227 | SCV000506552 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440902 | SCV000506553 | likely pathogenic | Neoplasm of uterine cervix | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419344 | SCV000506554 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430065 | SCV000506555 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439826 | SCV000506556 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422625 | SCV000506557 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432361 | SCV000506558 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439525 | SCV000506559 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Yale Center for Mendelian Genomics, |
RCV000029212 | SCV000611560 | pathogenic | Nevus sebaceous | 2012-10-25 | no assertion criteria provided | literature only | |
Institute of Medical Sciences, |
RCV001255682 | SCV001432247 | pathogenic | Lip and oral cavity carcinoma | 2019-04-30 | no assertion criteria provided | research | |
Yale Center for Mendelian Genomics, |
RCV001849283 | SCV002106447 | likely pathogenic | cutaneous-skeletal hypophosphatemia syndrome | 2016-08-01 | no assertion criteria provided | literature only |