10-110964362-A-G
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS4PS3PM2PS2PP2
This summary comes from the ClinGen Evidence Repository: The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146). The p.Ser2Gly variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data GTR ID's: 506381, 28338; PMID:25563136, 24458587). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID:19684605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SHOC2 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, PS3, PS4, PM2, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA118524/MONDO:0054637/004
Frequency
Consequence
NM_007373.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460838Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726742
GnomAD4 genome 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
Noonan syndrome-like disorder with loose anagen hair 1 Pathogenic:24Other:1
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Based on the classification scheme VCGS_Germline_v1.3.3, 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 Noonan syndrome-like with loose anagen hair (MIM#607721). Missense variants in this gene result in enhanced MAPK activation (OMIM, PMID: 19684605). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to glycine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and is observed in de novo patients with RASopathy (ClinVar, PMID: 25331583). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies have demonstrated this variant causes impaired nuclear translocation and MAPK activation (PMID: 19684605). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in multiple patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146). The p.Ser2Gly variant has been identified in at least 5 independent occurrences in patients with clinical features of a RASopathy (PS4; Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data GTR ID's: 506381, 28338; PMID: 25563136, 24458587). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the SHOC2 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, PS3, PS4, PM2, PP2. -
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PP2,PP3,PP4,PP5. -
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PS2_VeryStrong, PS3, PS4, PM2, PP2 -
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The SHOC2 c.4A>G; p.Ser2Gly variant (rs267607048) has been reported in multiple individuals diagnosed with Noonan-like syndrome with loose anagen hair, and often identified as a de novo alteration (Cordeddu 2009, Komatsuzaki 2010, Ekvall 2011, Gripp 2013, Baldassare 2014). Functional characterization of the p.Ser2Gly protein indicates enhanced myristoylation, and aberrant targeting of the SHOC2 to the cell membrane in the absence of growth factor signaling (Cordeddu 2009). This results in an increase in basal and growth-factor stimulated ERK phosphorylation (Cordeddu 2009), consistent with the established disease mechanisms. The variant is classified as pathogenic by many sources in the ClinVar database (Variation ID: 6821) is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is classified as pathogenic. References: Baldassarre G et al. Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation. Am J Med Genet A. 2014 Dec;164A(12):3120-5. PMID: 25331583. Cordeddu V et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009 Sep;41(9):1022-6. PMID: 19684605. Ekvall S et al. Co-occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype. Am J Med Genet A. 2011 Jun;155A(6):1217-24. PMID: 21548061. Gripp KW et al. Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis. Am J Med Genet A. 2013 Oct;161A(10):2420-30. PMID: 23918763. Komatsuzaki S et al. Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. J Hum Genet. 2010 Dec;55(12):801-9. PMID: 20882035. -
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The missense c.4A>G(p.Ser2Gly) variant in SHOC2 gene has been reported previously in individual(s) affected with Noonan syndrome with loose anagen hair (Gripp KW, et. al., 2013; Choi JH, et. al., 2015). Functional studies indicate that this variant has a damaging effect on the gene or the gene product (Cordeddu V, et. al., 2009). The p.Ser2Gly variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has been submitted to ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Ser2Gly in SHOC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 2 is changed to a Gly 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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The SHOC2 c.4A>G (p.Ser2Gly) variant has been reported in multiple individuals with clinical features of a RASopathy and is reported as occurring de novo in at least three individuals (Choi JH et al., PMID: 25563136; Cordeddu V et al., PMID: 19684605; Ekvall S et al., PMID: 21548061; Gargano G et al., PMID: 24458587; Gripp KW et al., PMID: 23918763). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by 40 submitters including a classification of pathogenic by the ClinGen RASopathy Expert Panel. In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (Cordeddu V et al., PMID: 19684605). The SHOC2 gene has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variation and pathogenic missense variants are a common mechanism of disease (Gelb BD et al., PMID: 29493581). Based on available information, the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), and the RASopathy Expert Panel consensus methods (Gelb BD et al., PMID: 29493581), this variant is classified as pathogenic. -
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ACMG classification criteria: PS2 very strong, PS3 moderate, PS4 moderate, PM2 moderate, PP2 supporting -
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PS2, PM2, PP3, PP5 -
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Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 22528146, 21548061, 23918763, 19684605, 25563136, 24458587, PS2, PS4). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19684605, PS3). 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 observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000319, PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:10
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PS2, PS3, PS4, PM6_Strong, PM1, PP2 -
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Located in the critical functional domain S2 and inhibits SHOC2 function by impairing proper cellular localization of the protein (Galperin et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25858597, 22419608, 26350204, 24803665, 31501239, 19684605, 22606262, 25846317, 25563136, 21548061, 24033266, 25326637, 24458596, 24458587, 25331583, 23918763, 25123707, 26096762, 22528146, 26607044, 26519477, 20882035, 22995099, 28680615, 28554332, 24124081, 29737035, 29948256, 30732632, 30240112, 30417923, 30050098, 29907801, 31219622, 30962759, 31584751, 31628766, 31019026, 32005694, 33318624, 34008892, 33300679, 33502061, 32978145, 33240318, 32870709, 34006472, 31785789) -
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This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene (PMID: 19684605, 25846317, 25331583, 25123707). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 19684605, 22606262).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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RASopathy Pathogenic:3
This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 2 of the SHOC2 protein (p.Ser2Gly). This variant is present in population databases (rs267607048, gnomAD 0.007%). This missense change has been observed in individual(s) with Noonan-like syndrome with loose anagen hair (PMID: 19684605, 20882035, 22995099, 23918763, 25123707, 25331583). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6821). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SHOC2 function (PMID: 19684605, 22606262). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: SHOC2 c.4A>G (p.Ser2Gly) results in a non-conservative amino acid change in the encoded protein sequence, located in the N-terminal region. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248040 control chromosomes. The variant has been reported in literature as one of the most recurrent mutations found in patients with NS or NS-related disorders. It is predominantly found in patients with Noonan-like syndrome with loose anagen hair. The variant was proven to be de novo in multiple patients strongly supporting its pathogenicity. From functional studies this variant was found to introduce an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation. Expression of SHOC2-S2G in vitro enhanced MAPK activation in a cell type specific fashion. Induction of SHOC2-S2G in Caenorhabditis elegans engendered protruding vulva, a neomorphic phenotype associated with aberrant signaling (Cordeddu_2009). In other functional study, the SHOC2-S2G mutant did not rescue ERK1/2 activation in Shoc2-depleted cells and the mutant was not located in late endosomes, however it was present on the plasma membrane and early endosomes (Galperin_2012). 13 clinical diagnostic laboratories (including one expert panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Variant classified using ACMG guidelines -
Noonan syndrome Pathogenic:2
The p.Ser2Gly variant in SHOC2 is an established pathogenic variant for Noonan s yndrome with loose anagen hair. The variant was identified in >40 affected indiv iduals across multiple studies and in multiple cases was shown to be de novo (Co rdeddu 2009, Komatsuzaki 2010, Gripp 2013, LMM data). It has not been identified large population studies. In vitro functional studies provide some evidence tha t the p.Ser2Gly variant impacts protein function (Cordeddu 2009). In summary, th is variant meets our criteria to be classified as pathogenic for Noonan syndrome in an autosomal dominant manner. -
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Inborn genetic diseases Pathogenic:1
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Polycystic kidney disease 4 Pathogenic:1
PS2, PS4, PM2 -
SHOC2-related disorder Pathogenic:1
The SHOC2 c.4A>G variant is predicted to result in the amino acid substitution p.Ser2Gly. This variant was initially identified in four unrelated individuals with Noonan-like syndrome, three of which were confirmed to be de novo events (Cordeddu et al. 2009. PubMed ID: 19684605), and has since been repeatedly documented as pathogenic in multiple unrelated individuals (Cordeddu et al. 2009. PubMed ID: 19684605; Hoban et al. 2012. PubMed ID: 22528146; Bessis et al. 2019. PubMed ID: 30417923; Leach et al. 2019. PubMed ID: 29907801). Functional studies found that this variant results in aberrant targeting of SHOC2 protein to the plasma membrane, impaired translocation to the nucleus upon growth factor stimulation, and enhanced MAPK activation in a cell type specific manner (Cordeddu et al. 2009. PubMed ID: 19684605). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as pathogenic by multiple labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6821/). This variant is interpreted as pathogenic. -
Noonan syndrome-like disorder with loose anagen hair Pathogenic:1
This variant has been previously reported as a de novo change in multiple unrelated patients with Noonan-like syndrome with loose anagen hair (PMID: 19684605, 25331583). This variant has been classified in ClinVar as pathogenic by the ClinGen Rasopathy Expert Panel and by several clinical diagnostic laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6821/). It is present in one heterozygote in the gnomAD population database 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, this variant is classified as pathogenic. -
Pectus excavatum;C4478716:Noonan syndrome-like disorder with loose anagen hair 1 Pathogenic:1
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Noonan syndrome and Noonan-related syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at