ClinVar Miner

Submissions for variant NM_007373.3(SHOC2):c.4A>G (p.Ser2Gly) (rs267607048)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506658 SCV000605107 pathogenic not specified 2016-10-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000624656 SCV000741813 pathogenic Inborn genetic diseases 2017-02-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Baylor Genetics RCV000149834 SCV000196678 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Baylor Genetics RCV000007223 SCV000807267 pathogenic Noonan syndrome-like disorder with loose anagen hair 1 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found twice in our laboratory de novo: in a 12-year-old male with moyamoya, Dandy-Walker variant, craniosynostosis, aortic root dilatation, macrocephaly, CHD, possible left duplex collecting system, dysmorphisms, spasticity, global delays, joint laxity, sparse sclp hair, webbed neck, cafe au lait spots, penile skin bridges; in a 6-year-old female with clinical diagnosis of Noonan syndrome
Blueprint Genetics RCV000208379 SCV000264222 pathogenic Noonan syndrome 2015-01-26 criteria provided, single submitter clinical testing
ClinGen RASopathy Variant Curation Expert Panel RCV000007223 SCV000616382 pathogenic Noonan syndrome-like disorder with loose anagen hair 1 2017-04-03 reviewed by expert panel curation 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000213000 SCV000332269 pathogenic not provided 2015-06-15 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000007223 SCV000965711 pathogenic Noonan syndrome-like disorder with loose anagen hair 1 2015-01-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000007223 SCV000611318 pathogenic Noonan syndrome-like disorder with loose anagen hair 1 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000213000 SCV000209051 pathogenic not provided 2018-05-15 criteria provided, single submitter clinical testing The Ser2Gly missense pathogenic variant in the SHOC2 gene accounts for approximately 5% of all patients with a Noonan-like phenotype and negative results for analysis of the PTPN11, SOS1, RAF1, and KRAS genes (Cordeddu et al., 2009). This variant typically has a distinct clinical presentation, including features of Noonan syndrome and loose anagen hair, in association with one or more of the following features: distinctive hyperactive behavior, mitral valve dysplasia and septal cardiac defects. The S2G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies have shown that S2G variant inhibits SHOC2 function by impairing proper cellular localization of the protein (Galperin et al., 2012).
Genetic Services Laboratory, University of Chicago RCV000007223 SCV000248876 pathogenic Noonan syndrome-like disorder with loose anagen hair 1 2015-03-13 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000007223 SCV000265524 pathogenic Noonan syndrome-like disorder with loose anagen hair 1 2014-09-11 criteria provided, single submitter research
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000007223 SCV000143830 not provided Noonan syndrome-like disorder with loose anagen hair 1 no assertion provided not provided
Integrated Genetics/Laboratory Corporation of America RCV000588131 SCV000699328 pathogenic Noonan syndrome 3 2016-07-11 criteria provided, single submitter clinical testing Variant summary: The SHOC2 c.4A>G (p.Ser2Gly) variant involves the alteration of a highly conserved nucleotide. It is located in N-terminal region however has not been reported to lie in any known protein domain in databases UniProt, Entrez and Ensemble. 4/5 in silico tools predict a damaging outcome. 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). This variant is absent from approximately 111676 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. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "Pathogenic". Taken together, this variant is classified as Pathogenic.
Invitae RCV000149834 SCV000253914 pathogenic Rasopathy 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 2 of the SHOC2 protein (p.Ser2Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. This variant is not present in population databases (rs267607048, ExAC no frequency). This variant has been reported in many individuals affected with Noonan-like syndrome with loose anagen hair (PMID: 19684605, 23918763, 22995099, 25331583, 25123707). In several of these individuals, this variant was shown to arise de novo (PMID: 19684605, 20882035). ClinVar contains an entry for this variant (Variation ID: 6821). Experimental studies have shown that this missense change causes aberrant processing and localization of the SHOC2 protein upon growth factor stimulation (PMID: 19684605, 22606262) and is unable to rescue the phenotype of SHOC2 depletion in C. elegans (PMID: 19684605). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000208379 SCV000062456 pathogenic Noonan syndrome 2014-12-03 criteria provided, single submitter clinical testing 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.
Laboratory of Molecular Genetics (Pr. Bezieau's lab),CHU de Nantes RCV000213000 SCV000920499 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000007223 SCV000263045 likely pathogenic Noonan syndrome-like disorder with loose anagen hair 1 2015-07-20 criteria provided, single submitter clinical testing
OMIM RCV000007223 SCV000027419 pathogenic Noonan syndrome-like disorder with loose anagen hair 1 2013-10-01 no assertion criteria provided literature only
UCLA Clinical Genomics Center, UCLA RCV000007223 SCV000255466 likely pathogenic Noonan syndrome-like disorder with loose anagen hair 1 2013-11-26 criteria provided, single submitter clinical testing

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