11-534285-C-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001318054.2(HRAS):c.-282G>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001318054.2 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HRAS | ENST00000311189.8 | c.38G>T | p.Gly13Val | missense_variant | Exon 2 of 6 | 1 | NM_005343.4 | ENSP00000309845.7 | ||
HRAS | ENST00000417302.7 | c.38G>T | p.Gly13Val | missense_variant | Exon 2 of 6 | 5 | NM_176795.5 | ENSP00000388246.1 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Costello syndrome Pathogenic:3
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. -
- -
PM2_Supporting+PS4_Supporting+PM6+PM5_Strong+PP3_Moderate -
not provided Pathogenic:3
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). -
HRAS: PM1, PM2, PM5, PS4:Moderate, PP2, PP3, PS2:Supporting -
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. -
Linear nevus sebaceous syndrome Pathogenic:1
Variant confirmed as disease-causing by referring clinical team -
KA-like vemurafenib-induced squamous lesions Pathogenic:1
- -
Lip and oral cavity carcinoma Pathogenic:1
- -
Large congenital melanocytic nevus Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at