11-534289-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_005343.4(HRAS):c.34G>A(p.Gly12Ser) variant causes a missense 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12A) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 34)
Consequence
HRAS
NM_005343.4 missense
NM_005343.4 missense
Scores
9
5
4
Clinical Significance
Conservation
PhyloP100: 6.09
Genes affected
HRAS (HGNC:5173): (HRas proto-oncogene, GTPase) This gene belongs to the Ras oncogene family, whose members are related to the transforming genes of mammalian sarcoma retroviruses. The products encoded by these genes function in signal transduction pathways. These proteins can bind GTP and GDP, and they have intrinsic GTPase activity. This protein undergoes a continuous cycle of de- and re-palmitoylation, which regulates its rapid exchange between the plasma membrane and the Golgi apparatus. Mutations in this gene cause Costello syndrome, a disease characterized by increased growth at the prenatal stage, growth deficiency at the postnatal stage, predisposition to tumor formation, cognitive disability, skin and musculoskeletal abnormalities, distinctive facial appearance and cardiovascular abnormalities. Defects in this gene are implicated in a variety of cancers, including bladder cancer, follicular thyroid cancer, and oral squamous cell carcinoma. Multiple transcript variants, which encode different isoforms, have been identified for this gene. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
In a strand (size 3) in uniprot entity RASH_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) in NM_005343.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-534288-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 12603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98
PP5
Variant 11-534289-C-T is Pathogenic according to our data. Variant chr11-534289-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12602.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-534289-C-T is described in UniProt as null. Variant chr11-534289-C-T is described in UniProt as null. Variant chr11-534289-C-T is described in UniProt as null. Variant chr11-534289-C-T is described in UniProt as null. Variant chr11-534289-C-T is described in UniProt as null. Variant chr11-534289-C-T is described in UniProt as null. Variant chr11-534289-C-T is described in Lovd as [Pathogenic]. Variant chr11-534289-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-534289-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| HRAS | NM_005343.4 | c.34G>A | p.Gly12Ser | missense_variant | 2/6 | ENST00000311189.8 | |
| HRAS | NM_176795.5 | c.34G>A | p.Gly12Ser | missense_variant | 2/6 | ENST00000417302.7 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HRAS | ENST00000311189.8 | c.34G>A | p.Gly12Ser | missense_variant | 2/6 | 1 | NM_005343.4 | P1 | |
| HRAS | ENST00000417302.7 | c.34G>A | p.Gly12Ser | missense_variant | 2/6 | 5 | NM_176795.5 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:68
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Costello syndrome Pathogenic:24
| Pathogenic, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The c.34G>A (p.Gly12Ser) variant in HRAS has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 16170316, 16835863, 16443854, 16835863, 16881968, 17054105, 19669404). The p.Gly12Ser variant has been identified in >5 independent occurrences in patients with clinical features of a RASopathy (PS4; PMID: 20660566, 16372351, 16329078, 16969868, 18039947, 19371735, 19206176, 16835863). In vitro functional studies provide some evidence that the p.Gly12Ser variant may impact protein function (PS3; PMID: 17412879). Computational prediction tools and conservation analysis suggest that the p.Gly12Ser variant may impact the protein (PP3). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the HRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PS3, PM1, PM2, PP2, PP3. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 24, 2018 | The HRAS c.34G>A p.(Gly12Ser) missense variant has been identified in individuals with a phenotype consistent with Costello syndrome, and in a de novo state in the majority (Gripp et al. 2006; Hague et al. 2017; Chiu et al. 2016; Niihori et al. 2011; van Steensel et al. 2006). This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Gly12 residue is highly conserved through evolution. Functional studies found that when the p.Gly12Ser variant HRAS protein was over-expressed in human diploid fibroblasts, cells exhibited a senescence phenotype including a flat, enlarged and multivacuolated morphology with prominent nucleoli, in contrast to cells produced by wild type HRAS protein (Niihori et al. 2011). In addition, cells expressing the p.Gly12Ser variant HRAS protein exhibited increased cell proliferation and astrogenesis, but decreased neurogenesis (Paquin et al. 2009). The variant was identified in a de novo state in the proband. Based on the available evidence, the p.Gly12Ser variant is classified as pathogenic for Costello syndrome. - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the HRAS protein (p.Gly12Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12602). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt HRAS function. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Jun 04, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 30, 2012 | The Gly12Ser variant in HRAS is the most common variant associated with Costello syndrome (Aoki 2005, Kerr 2006, Gripp 2006, Gori 2008, Dileone 2010, Estep 2006 , Gripp 2006, Lo 2008, Paquin 2009, Sol-Church 2009, Sol-Church 2006, van der Bu rgt 2007, van Steensel 2006, Zampino 2007, Zhang 2009). This variant has been re ported to have occurred de novo in many individuals. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 01, 2021 | PS1, PM1, PM2, PM5, PP2, PP3, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 16835863, 20660566, 19206176, 16329078, 16969868, 19371735, 18039947, 16372351, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17412879, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.695, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Costello syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012600, VCV000012603, VCV000012612, VCV000012613, VCV000040430, VCV000163690, VCV000180854, VCV000279921, VCV001209208, PM5_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012602, PS1_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 21, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Apr 01, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Jul 03, 2018 | This established pathogenic variant is found in approximately 80% of individuals with Costello syndrome (PMID: 16170316, 22261753, 20301680). This variant has been classified in ClinVar as pathogenic by the ClinGen Rasopathy Expert Panel and by several clinical diagnostic laboratories (variant ID: 12602). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.34G>A (p.Gly12Ser) variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 13, 2019 | Variant summary: HRAS c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250394 control chromosomes (gnomAD). The variant, c.34G>A, has been reported in the literature in multiple individuals affected with Costello Syndrome (Aoki_2005, Kerr_2006, Gripp_2006, Niihori_2011). These data indicate that the variant is very likely to be associated with disease. At least two publication report experimental evidence evaluating an impact on protein function (Gain of function) and the effect of this variant is similar to other HRAS pathogenic variants (Paquin_2009, Niihori_2011). Eight ClinVar submissions from clinical diagnostic laboratories and one expert panel (ClinGen RASopathy) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Mar 01, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center | Dec 18, 2019 | The missense variant c.34G>A results in a single base pair substitution at nucleotide position 34 in exon 2 (6 in total) of_x000D_the HRAS gene. The c.34G>A variant is not observed in the Genome Aggregation Database (gnomAD), indicating it is_x000D_not a common benign variant in the populations represented in this database._x000D_The variant is a well-defined pathogenic variant associated with Costello syndrome (PMID:NBK1507), and has been_x000D_described as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (VarID: 12602). It has been reported_x000D_previously in multiple patients with features of RASopathy (PMID: 16170316, 16835863, 16443854, 16881968,_x000D_17054105). The variant is located in a mutational hotspot region, which harbors very low rate of benign missense_x000D_mutations. This variant is predicted to be deleterious by multiple computational tools. Additionally, in vitro functional_x000D_studies have demonstrated that this variant may affect protein function (PMID: 17412879) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 16, 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 and congenital myopathy with excess of muscle spindles (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 (PMID: 20301680). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (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) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple alternative changes at this residue have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel and multiple clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jun 07, 2022 | PS2 PS3 PS4 PM2 PM5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 29, 2019 | - - |
| Pathogenic, no assertion criteria provided | research | Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University | Oct 14, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Apr 06, 2018 | [ACMG/AMP: PS2, PM1, PM2, PM5, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Jan 11, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Dec 18, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense c.34G>A(p.Gly12Ser) variant in HRAS gene has been reported previously in individual(s) affected with Costello syndrome (Niihori T, et. al., 2011; Aoki Y, et. al., 2005). Functional studies indicate this variant has a damaging effect on the gene or the gene product (van der Burgt I, et. al., 2007). The p.Gly12Ser variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid Gly at position 12 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:7
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 29, 2019 | Functional studies indicate that the G12S variant alters GTP and GDP dissociation rates resulting in increased active GTP-bound HRAS, which up-regulates the Ras/MAPK pathway (Wey et al. 2013); Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Classified as pathogenic by the ClinGen RASopathy Expert Panel (SCV000616364.3; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 22317973, 27195699, 21850009, 24224811, 23093928, 16329078, 16170316, 19371735, 23751039, 21834037, 20979192, 27705751, 26350204, 24803665, 27589201, 25722179, 24169525, 28141901, 28027064, 16835863, 17412879, 16881968, 19669404, 30138938, 30055033, 30792901, 30050098, 25815234, 31394527, 29907801, 31560489, 31564432, 31712860, 31965297, 31795565, 32369273, 32371413, 33482860, 32681669) - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 16, 2020 | The HRAS c.34G>A; p.Gly12Ser variant (rs104894229) is a very common pathogenic variant in patients diagnosed with Costello syndrome (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011, Zampino 2007). The glycine residues at codons 12 and 13 are frequently altered in both Costello syndrome patients (Aoki 2005, Estep 2006, Gripp 2005, Kerr 2006, Niihori 2011) and tumor samples (Aoki 2005, Estep 2006). Functional characterization of the p.Gly12Ser protein indicates increased downstream MEK signaling activity (Aoki 2005, Niihori 2011), consistent with the established disease mechanism of Costello syndrome, which has phenotypic overlap with Noonan syndrome. Based on available information, this variant is considered to be pathogenic. References: Aoki Y et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet. 2005; 37(10):1038-40. Estep A et al. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am J Med Genet A. 2006; 140(1):8-16. Gripp K et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006; 140(1):1-7. Kerr B et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006; 43(5):401-5. Niihori T et al. HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome. J Hum Genet. 2011; 56(10):707-15. Zampino G et al. Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome. Hum Mutat. 2007; 28(3):265-72. - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 10, 2021 | Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID 28139825). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in approximately 80% of individuals with Costello syndrome and is reported to be the most frequent pathogenic variant in the HRAS gene (PMID: 21834037, 20979192, 17054105, 16881968, 16372351, 16170316, 16329078, 16443854). This variant occurs de novo in an individual tested at Athena Diagnostics and in previously reported individuals with clinical features of Costello syndrome (PMID: 16170316, 16372351, 16881968, 17054105, 21834037, 28027064). Germline mosaicism has been reported as an inheritance mechanism for multiple cases, with the majority arising in the paternal germline (PMID: 24259709, 16835863, 21834037).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 27, 2015 | - - |
Myelodysplastic syndrome Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Glioblastoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Prostate adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Noonan syndrome 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics, Centre for Human Genetics | - | - - |
Carcinoma of esophagus Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell carcinoma of the skin Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Gastric adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Breast neoplasm Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Myopathy, congenital, with excess of muscle spindles Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2014 | - - |
HRAS-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 29, 2024 | The HRAS c.34G>A variant is predicted to result in the amino acid substitution p.Gly12Ser. This variant is one of the most frequent pathogenic variants in HRAS and has been documented as a de novo event in multiple unrelated individuals with Costello Syndrome (for examples see - Aoki et. al. 2005. PubMed ID: 17177115; Gripp et al. 2011. PubMed ID: 21834037). Additionally, different amino acid substitutions (p.Gly12Arg, p.Gly12Cys, p.Gly12Asp, p.Gly12Ala, p.Gly12Val) affecting the same amino acid have been reported as pathogenic (Human Gene Mutation Database). Functional studies demonstrate increased GTP-bound HRAS (active state) in cells transfected with the p.Gly12Ser variant, consistent with a gain-of-function mechanism that results in the hyperactivation of the RAS pathway (Niihori et al. 2011. PubMed ID: 21850009). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant has been interpreted by multiple labs and the ClinGen RASopathy Variant Curation Expert Panel as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12602/). This variant is interpreted as pathogenic. - |
Multiple myeloma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Nasopharyngeal neoplasm Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Epidermal nevus Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Sep 07, 2023 | An HRAS c.34G>A (p.Gly12Ser) variant was identified. This variant has been reported in numerous individuals with epidermal nevus (Hafner C et al., PMID: 22087699; Farschtschi S et al., PMID: 25928347; Nishihara K et al., PMID: 30864170; Levinsohn JL et al., PMID: 24129065; Honda A et al., PMID: 28295558; Bender RP et al., PMID: 23599145). This variant has been reported in the ClinVar database as a germline pathogenic variant by numerous submitters, including an expert panel (ClinVar ID: 12602) and has been reported as a somatic variant in multiple cases in the cancer database cBioPortal. This variant is absent from the general population (gnomAD v.3.1.2), indicating that it is not a common variant. Other variants in the same codon, (p.Gly12Arg, p.Gly12Cys, p.Gly12Val, p.Gly12Ala, p.Gly12Asp), have been reported as pathogenic/likely pathogenic [ClinVar ID: 375961, 12613, 12600, 1209208, 12603, 40430, 12612]. The HRAS c.34G>A (p.Gly12Ser) variant resides within an H_N_K_Ras_like domain, amino acids 3-164, of HRAS that is defined as a critical functional domain (Wey M et al., PMID: 24224811). Functional studies show that this variant promotes enhanced MEK, ERK, and AKT phosphorylation and growth-factor independent proliferation, indicating that this variant impacts protein function (Gremer L et al., PMID: 19995790; Denayer E et al., PMID: 17979197). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to HRAS function. 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.34G>A (p.Gly12Ser) variant is classified as pathogenic. - |
Adenoid cystic carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 08, 2023 | The c.34G>A (p.G12S) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to A substitution at nucleotide position 34, causing the glycine (G) at amino acid position 12 to be replaced by a serine (S). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration and several other alterations at the same codon (p.G12A, p.G12C, p.G12D, p.G12E, and p.G12V) have been reported in individuals with HRAS-related RASopathy including many de novo occurrences (Aoki, 2005; Hoornaert, 2006; Gripp, 2006; Lo, 2008; Burkitt-Wright, 2012). The p.G12S alteration is the most prevalent alteration reported in patients with HRAS-related RASopathy (reviewed in Wey, 2013). This amino acid position is highly conserved in available vertebrate species. The p.G12 amino acid is located within the phosphate-binding loop of the GTP-binding site (Gripp, 2006). Functional analysis demonstrated that protein products containing the p.G12S alteration have increased binding of GTP, resulting in increased amounts of the active form the HRAS protein (Wey, 2013). Additionally, patient cell lines with the p.G12S alteration were found to have reduced expression of C4ST-1 mRNA compared to wild type (Kluppel 2012), and in vivo studies showed abnormal neuronal cell proliferation and astrogenesis (Paquin, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. - |
Wooly hair nevus Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2014 | - - |
Hepatocellular carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of the large intestine Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Papillary renal cell carcinoma, sporadic Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Nevus sebaceous Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2014 | - - |
Rhabdomyosarcoma Pathogenic:1
| Pathogenic, no assertion criteria provided | provider interpretation | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 01, 2020 | - - |
Ovarian serous cystadenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Malignant melanoma of skin Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Uterine carcinosarcoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Lip and oral cavity carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Institute of Medical Sciences, Banaras Hindu University | Apr 30, 2019 | - - |
Acute myeloid leukemia Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Malignant neoplasm of body of uterus Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Epidermal nevus with urothelial cancer, somatic Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2014 | - - |
Pancreatic adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
See cases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | Dec 21, 2022 | - - |
Lung adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of uterine cervix Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Transitional cell carcinoma of the bladder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Squamous cell carcinoma of the head and neck Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Thyroid tumor Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Noonan syndrome and Noonan-related syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 19, 2016 | - - |
RASopathy Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | - | Variant classified using ACMG guidelines - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;.;D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
N;N;N;N;N
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
P;P;P;P;P
Vest4
MutPred
Gain of glycosylation at G12 (P = 0.0044);Gain of glycosylation at G12 (P = 0.0044);Gain of glycosylation at G12 (P = 0.0044);Gain of glycosylation at G12 (P = 0.0044);Gain of glycosylation at G12 (P = 0.0044);
MVP
MPC
1.6
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at