11-534289-C-T
Variant summary
Our verdict is Pathogenic. The variant received 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. G12V) has been classified as Pathogenic.
Frequency
Consequence
NM_005343.4 missense
Scores
Clinical Significance
Conservation
Publications
- ciliary dyskinesia, primary, 39Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- primary ciliary dyskinesiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 33
GnomAD4 genome
ClinVar
Submissions by phenotype
Costello syndrome Pathogenic:24
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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). -
PS1, PM1, PM2, PM5, PP2, PP3, PP5 -
PS2 PS3 PS4 PM2 PM5 -
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. -
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
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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. -
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). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt HRAS function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
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. -
[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]. -
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 -
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) -
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The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID: 29493581). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17412879). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012602 /PMID: 16170316 /3billion dataset). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 16170316, 16443854, 16835863, 16881968, 17054105, 19669404). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16329078, 16372351, 16835863, 16969868, 18039947, 19206176, 19371735, 20660566). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Gly12Ala, p.Gly12Arg, p.Gly12Asp, p.Gly12Cys, p.Gly12Glu, p.Gly12Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012600, VCV000012603, VCV000012612, VCV000012613, VCV000040430, VCV000163690, VCV000180854, VCV000279921, VCV000375961, VCV001209208 /PMID: 16155195, 16170316, 16443854, 18039947, 22495892, 27195699, 28489335 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
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. -
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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. -
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not provided Pathogenic:7
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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. -
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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) -
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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. -
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Noonan syndrome 1 Pathogenic:2
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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). 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. -
Nevus sebaceous Pathogenic:1
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Rhabdomyosarcoma Pathogenic:1
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Myopathy, congenital, with excess of muscle spindles Pathogenic:1
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Lip and oral cavity carcinoma Pathogenic:1
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HRAS-related disorder Pathogenic:1
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. -
Epidermal nevus with urothelial cancer, somatic Pathogenic:1
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See cases Pathogenic:1
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Epidermal nevus Pathogenic:1
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. -
Wooly hair nevus Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
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. -
Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0587248:Costello syndrome;C1842036:Large congenital melanocytic nevus;C4225426:Thyroid cancer, nonmedullary, 2;C4552097:Linear nevus sebaceous syndrome Pathogenic:1
PM2_Supporting+PS4+PS2+PP3+PM1 -
Noonan syndrome and Noonan-related syndrome Pathogenic:1
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RASopathy Pathogenic:1
Variant classified using ACMG guidelines -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at