11-534288-C-T
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_005343.4(HRAS):c.35G>A(p.Gly12Asp) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12S) has been classified as Pathogenic.
Frequency
Consequence
NM_005343.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HRAS | NM_005343.4 | c.35G>A | p.Gly12Asp | missense_variant | 2/6 | ENST00000311189.8 | |
HRAS | NM_176795.5 | c.35G>A | p.Gly12Asp | missense_variant | 2/6 | ENST00000417302.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HRAS | ENST00000311189.8 | c.35G>A | p.Gly12Asp | missense_variant | 2/6 | 1 | NM_005343.4 | P1 | |
HRAS | ENST00000417302.7 | c.35G>A | p.Gly12Asp | missense_variant | 2/6 | 5 | NM_176795.5 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Costello syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 09, 2019 | This sequence change replaces glycine with aspartic acid at codon 12 of the HRAS protein (p.Gly12Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many individuals affected with Costello syndrome (PMID: 26916728, 18642361, 21850009, 27102959, 18039947, 22926243). In several individuals the variant was found to be de novo. ClinVar contains an entry for this variant (Variation ID: 12612). This variant has been reported to affect HRAS protein function (PMID: 24224811, 21850009). This variant disrupts the p.Gly12 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Costello syndrome (MIM#218040) (PMID: 31222966). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been observed in at least ten Costello syndrome patients, in some of whom de novo inheritance was reported (PMID: 22926243, 26916728, 27102959; ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic (SCV000207860, PS1). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change (p.Gly12Val, p.Gly12Ala, p.Gly12Glu, p.Gly12Cys) at the same codon has been reported as pathogenic (ClinVar ID: VCV000012600.3, VCV000040430.1, VCV000163690.1, VCV000012613.12, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.781, 3Cnet: 0.996, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 09, 2011 | The Gly12Asp variant in HRAS has been reported in the literature in four individ uals with severe neonatal Costello syndrome (Lo 2008, Kuniba 2009, Sinico 2010). This variant has been reported to have occurred de novo in two probands (Lo 200 8, Sinico 2010). This variant has been observed as a somatic change in tumor tis sue. Several other variants in codon 12 of HRAS are commonly observed in Costell o syndrome patients (Lin 2011). Therefore, it is highly likely that this variant is pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2022 | Functional studies show p.(G12D) results in increased levels of the active, GTP-bound HRAS protein (PMID: 21850009); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18642361, 35050212, 24224811, 23093928, 18039947, 22926243, 24803665, 26916728, 21344638, 17979197, 20658932, 32304219, 33502061, 33932139, 33726816, 35584285, 34958143, 21850009, 29493581) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2019 | - - |
RASopathy Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | - | Variant classified using ACMG guidelines - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 30, 2017 | Variant summary: The HRAS c.35G>A (p.Gly12Asp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 276492 control chromosomes. It has been reported in many CS cases and most of them with severe clinical presentations. Functional assays showed the variant to have increased activity (Niihori_2011). Variants involving codon 12 (such as p.G12S, p.G12A, p.G12C, p.G12D) have been reported in numerous affected individuals indicating it is mutation hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Costello syndrome, severe Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 10, 2012 | - - |
Nevus sebaceous Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 10, 2012 | - - |
Breast neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Non-immune hydrops fetalis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Apr 30, 2020 | - - |
Lip and oral cavity carcinoma Pathogenic:1
Pathogenic, no assertion criteria provided | research | Institute of Medical Sciences, Banaras Hindu University | Apr 30, 2019 | - - |
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 06, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at