10-110964362-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP2 PP3_Moderate PP5_Very_Strong

The NM_007373.4(SHOC2):c.4A>G(p.Ser2Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S2T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SHOC2 NM_007373.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:40 O:1
• Conservation: PhyloP100: 8.49

Genes affected

SHOC2 (HGNC:15454): (SHOC2 leucine rich repeat scaffold protein) This gene encodes a protein that consists almost entirely of leucine-rich repeats, a domain implicated in protein-protein interactions. The protein may function as a scaffold linking RAS to downstream signal transducers in the RAS/ERK MAP kinase signaling cascade. Mutations in this gene have been associated with Noonan-like syndrome with loose anagen hair. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SHOC2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852
• PP5: Variant 10-110964362-A-G is Pathogenic according to our data. Variant chr10-110964362-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 6821.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr10-110964362-A-G is described in Lovd as [Pathogenic]. Variant chr10-110964362-A-G is described in Lovd as [Likely_pathogenic]. Variant chr10-110964362-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHOC2	NM_007373.4	c.4A>G	p.Ser2Gly	missense_variant	2/9	ENST00000369452.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHOC2	ENST00000369452.9	c.4A>G	p.Ser2Gly	missense_variant	2/9	1	NM_007373.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460838 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:40 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome-like disorder with loose anagen hair 1 Pathogenic:21 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 16, 2021	ACMG classification criteria: PS2 very strong, PS3 moderate, PS4 moderate, PM2 moderate, PP2 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jan 13, 2021	- -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	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 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 20, 2015	- -
Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 01, 2021	PS2, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jan 01, 2015	- -
not provided, no classification provided	literature only	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Nov 26, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Nov 21, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PP2,PP3,PP4,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 13, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 28, 2023	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. -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 11, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Feb 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	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. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
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	Mayo Clinic Laboratories, Mayo Clinic	Sep 09, 2019	PS2, PS3, PS4, PM6_Strong, PM1, PP2 -
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	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 15, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	Jul 19, 2018	- -

RASopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	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. -

Noonan syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 03, 2014	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 26, 2015	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2017

- -

Polycystic kidney disease 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Mar 30, 2022

PS2, PS4, PM2 -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 08, 2021

- -

Noonan syndrome-like disorder with loose anagen hair Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Feb 22, 2018

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

Pathogenic, criteria provided, single submitter

not provided

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.35	N;N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.60	T;T
Polyphen		0.92	P;P
Vest4		0.71
MutPred		0.74		Loss of phosphorylation at S2 (P = 0.0013);Loss of phosphorylation at S2 (P = 0.0013);
MVP		0.51
MPC		1.2
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.44
gMVP		0.017

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607048; hg19: chr10-112724120; COSMIC: COSV54624833; COSMIC: COSV54624833;