VCV000181528.21 - ClinVar

NM_007373.4(SHOC2):c.519G>A (p.Met173Ile)

Germline

Top reviewed classifications are shown here.

Submission summary:

10 submissions

10 submitters

7 conditions

Reviewed by expert panel

Pathogenic

Sep 2024 by ClinGen RASopa… FDA Recognized Database

for RASopathy

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_007373.4(SHOC2):c.519G>A (p.Met173Ile)

Variation ID: 181528 Accession: VCV000181528.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q25.2 10: 110964877 (GRCh38) [ NCBI UCSC ] 10: 112724635 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 1, 2015	Oct 13, 2024	Sep 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_007373.4:c.519G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_031399.2:p.Met173Ile	missense
NM_001269039.3:c.519G>A	NP_001255968.1:p.Met173Ile	missense
NM_001324336.2:c.519G>A	NP_001311265.1:p.Met173Ile	missense
NM_001324337.1:c.519G>A
NM_001324337.2:c.519G>A	NP_001311266.1:p.Met173Ile	missense
NC_000010.11:g.110964877G>A
NC_000010.10:g.112724635G>A
NG_028922.1:g.50335G>A
LRG_753:g.50335G>A
LRG_753t1:c.519G>A	LRG_753p1:p.Met173Ile
	Q9UQ13:p.Met173Ile

... more HGVS ... less HGVS

Protein change

M173I

Other names

p.M173I:ATG>ATA
NM_007373.3(SHOC2):c.519G>A

Canonical SPDI

NC_000010.11:110964876:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA199174 UniProtKB: Q9UQ13#VAR_074030 OMIM: 602775.0002 dbSNP: rs730881020 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SHOC2		No evidence available	No evidence available	GRCh38 GRCh37	517	555

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
RASopathy	Pathogenic (2)	reviewed by expert panel	Sep 17, 2024	RCV000523270.10
Noonan syndrome-like disorder with loose anagen hair 1	Likely pathogenic (3)	criteria provided, single submitter	Feb 8, 2024	RCV000169685.3
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 2, 2020	RCV001030821.1
not provided	Likely pathogenic (1)	criteria provided, single submitter	Oct 4, 2021	RCV000586119.7
Non-immune hydrops fetalis	Likely pathogenic (1)	criteria provided, single submitter	Jan 9, 2020	RCV001376015.1
Cardiovascular phenotype	Likely pathogenic (1)	criteria provided, single submitter	Nov 29, 2021	RCV002336369.2
See cases	Likely pathogenic (1)	criteria provided, single submitter	Dec 21, 2022	RCV003156077.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 17, 2024)	reviewed by expert panel (ClinGen RASopathy ACMG Specifications SHOC2 V2.1.0) Method: curation	RASopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV000616431.5 First in ClinVar: Dec 19, 2017 Last updated: Oct 13, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6b6330b2-05be-48be-a7e9-3e8e77d8e63b Comment: The c.519G>A variant in the SHOC2 gene is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 173 (p.Met173Ile). This … (more) The c.519G>A variant in the SHOC2 gene is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 173 (p.Met173Ile). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.768 (PP3). This variant has been identified as a de novo occurrence with confirmed parental relationships in 3 individuals and with unconfirmed parental relationships in 1 individual with RASopathy (PS2_VeryStrong; Invitae, GeneDx, Ambry, Genomic Medicine Lab; ClinVar SCV001573982.4, SCV000209055.14, SCV002641556.1, SCV001573024.1). This variant has been reported in more than 5 probands diagnosed with RASopathy (PS4; PMIDs: 25137548, 29907801; Invitae, GeneDx, UCSF Genomic Medicine Lab, LabCorp, Ambry; ClinVar SCV001573982.4, SCV000209055.14, SCV001573024.1, SCV000699327.2, SCV002641556.1). ERK phosphorylation assays showed that this variant decreases the ability of SHOC2 to accelerate ERK1/2 phosphorylation (PS3 not met, PMID: 25137548). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PM2_Supporting, PP3 (Specification Version 2.1, 09/17/2024) (less)
Likely pathogenic (Feb 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome-like disorder with loose anagen hair 1 Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV005045150.1 First in ClinVar: May 26, 2024 Last updated: May 26, 2024	Comment: The SHOC2 c.519G>A (p.Met173Ile) variant has been reported in the literature in at least three individuals affected with a RASopathy. One publication described the variant … (more) The SHOC2 c.519G>A (p.Met173Ile) variant has been reported in the literature in at least three individuals affected with a RASopathy. One publication described the variant occurring de novo in an affected individual and another publication described the variant in a reportedly affected father and daughter (Hannig V et al., PMID: 25137548; Motta M et al., PMID: 35348676). Additionally, this variant has been reported in the ClinVar database as a germline likely pathogenic variant by five sources and a variant of uncertain significance by three sources. Although the ClinGen RASopathy Variant Curation Expert Panel classifies this variant as a variant of uncertain significance, the classification is nearly seven years old and does not reference more current evidence. In at least one of the ClinVar entries, the submitter references internal data showing detection of the variant de novo and detection of the variant in multiple affected individuals. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to SHOC2 function. In support of this prediction, functional studies in transgenic zebrafish show the variant causes enhanced SHOC2 binding to both MRAS and PPP1CB, and the variant protein promotes increased EGF-stimulated MAPK signaling (Motta M et al., PMID: 35348676). Based on available information and the ACMG/AMP guidelines for variant interpretation and the RASopathy Variant Curation Expert Panel guidelines (Gelb BD et al., PMID: 29493581; Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. (less)
Uncertain significance (Apr 02, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699327.2 First in ClinVar: Mar 17, 2018 Last updated: Apr 15, 2020	Publications: PubMed (3) PubMed: 25137548‚ 29907801‚ 30348783 Comment: Variant Summary : SHOC2 c.519G>A (p.Met173Ile) results in a conservative amino acid change located in the Leucine-rich repeat (IPR001611) of the encoded protein sequence. Four … (more) Variant Summary : SHOC2 c.519G>A (p.Met173Ile) results in a conservative amino acid change located in the Leucine-rich repeat (IPR001611) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250232 control chromosomes (gnomAD). c.519G>A has been reported in the literature in a father and daughter who did not have classic symptoms of NS, CFC or NS/LAH, but displayed features overlapping all three conditions, with mild clinical manifestations (Hannig_2014). The variant was also reported by a ClinVar submitter in a proband with clinical features of a RASopathy (SCV000616431.3). A different variant affecting the same amino acid (c.517A>G, p.M173V) was confirmed as de novo occurrence in one individual with Noonan-like syndrome with loose anagen hair (NS/LAH) (PMID 22670144). These data indicate that the variant may be associated with disease. Functional studies have provided somewhat contradictory conclusions regarding the mechanism of action of this variant. Hannig et al (2014) in their study demonstrated the variant protein has impaired capacity to interact with protein phosphatase 1c (PP1c), leading to insufficient activation of RAF-1 kinase and is thus unable to fully rescue ERK1/2 activity in cells depleted of endogenous SHOC2. The authors concluded that the variant causes loss of function in the ERK1/2 pathway. A more recent study (Young_2018), concluded that M173I behaves as a gain-of-function mutant that has enhanced interaction with MRAS and PP1 and rescues ERK activation by upregulating the ERK pathway in SHOC2-deficient cells. The authors describe the variant as being only weakly activating, which could perhaps correlate with presence of mild symptoms in reported patients (e.g. Hannig_2014). Two ClinVar submitters including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as uncertain significance. Based on the insufficient clinical and contradictory functional evidence outlined above, the variant was classified as uncertain significance. (less)
Likely pathogenic (Oct 04, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000209055.14 First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023	Comment: Published as paternally inherited in an individual with some features suggestive of a RASopathy, whose father was reported to have intellectual disability, a high arched … (more) Published as paternally inherited in an individual with some features suggestive of a RASopathy, whose father was reported to have intellectual disability, a high arched palate, sparse hair, and clubbed nails, but no additional findings suggestive of a RASopathy (Hannig et al., 2014); Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate conflicting data regarding the variant's effect, with some data suggesting a gain of protein function and some data suggesting a loss of protein function (Hannig et al., 2014; Young et al., 2018). Of note, the only well-defined pathogenic variant in the SHOC2 gene known to cause a RASopathy is c.4 A>G (p.Ser2Gly), which results in altered protein localization rather than function (Cordeddu et al., 2009; Lee et al., 2011).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Classified as a variant of uncertain signficance by the ClinGen RASopathy Expert Panel (SCV000616431.1; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 25137548, 29907801, 30417923, 27574535, 30050098, 33106373, 30348783) (less)
Likely pathogenic (Dec 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: de novo	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV003845313.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023	Clinical Features: Cavernous hemangioma (present) , Decreased body weight (present) , Downslanted palpebral fissures (present) , High forehead (present) , High palate (present) , Long philtrum (present) … (more) Cavernous hemangioma (present) , Decreased body weight (present) , Downslanted palpebral fissures (present) , High forehead (present) , High palate (present) , Long philtrum (present) , Narrow jaw (present) , Narrow palate (present) , Overfolded helix (present) , Pulmonic stenosis (present) , Atrial septal defect, ostium secundum type (present) , Shallow orbits (present) , Short stature (present) , Sparse hair (present) , Supravalvar aortic stenosis (present) (less)
Pathogenic (Aug 10, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001573982.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 25137548‚ 30348783‚ 22670144‚ 29907801 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SHOC2 function (PMID: 25137548, 30348783). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SHOC2 protein function. ClinVar contains an entry for this variant (Variation ID: 181528). This missense change has been observed in individual(s) with clinical features of SHOC2-related conditions (PMID: 22670144, 25137548, 29907801; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 173 of the SHOC2 protein (p.Met173Ile). (less)
Likely pathogenic (Nov 29, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002641556.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 25137548‚ 30348783 Comment: The c.519G>A (p.M173I) alteration is located in exon 2 (coding exon 1) of the SHOC2 gene. This alteration results from a G to A substitution … (more) The c.519G>A (p.M173I) alteration is located in exon 2 (coding exon 1) of the SHOC2 gene. This alteration results from a G to A substitution at nucleotide position 519, causing the methionine (M) at amino acid position 173 to be replaced by an isoleucine (I). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with symptoms of Noonan-like disorder (Hannig, 2014; Ambry internal data, GeneDx pers comm, Invitae pers comm). The patient reported in Hannig, et al. (2014) had right optic nerve hypoplasia, macrocephaly, nystagmus and ptosis, speech delay, hyperactive behavior, sparse slow-growing hair, wide-spaced nipples, clubbed nails, and nonspecific findings on a brain MRI. Her height was normal. Her father was also heterozygous for this alteration and had intellectual disability, tall stature, high-arched palate, sparse hair, and clubbed nails. This amino acid position is highly conserved in available vertebrate species. Functional studies showed that the p.M173I mutant protein leads to dysregulation of the ERK1/2 pathway due to impaired capacity to interact with the catalytic subunit of protein phosphatase 1c and insufficient activation of RAF-1 kinase, suggesting loss-of-function as the mechanism of disease (Hannig, 2014). However, Young et al. (2018) found that p.M173I behaves as a gain-of-function mutant that has enhanced interaction with MRAS and PP1 and rescues ERK activation in SHOC2-deficient cells. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
Likely pathogenic (Jan 09, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Non-immune hydrops fetalis (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Genomic Medicine Lab, University of California San Francisco Study: CSER-P3EGS Accession: SCV001573024.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021
Pathogenic (Nov 01, 2014)	no assertion criteria provided Method: literature only	NOONAN SYNDROME-LIKE DISORDER WITH LOOSE ANAGEN HAIR 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001424913.1 First in ClinVar: Aug 02, 2020 Last updated: Aug 02, 2020	Publications: PubMed (2) PubMed: 25137548‚ 30348783 Comment on evidence: In a father and daughter with features overlapping those of Noonan syndrome, with sparse and slow-growing hair (NSLH1; 607721), Hannig et al. (2014) identified heterozygosity … (more) In a father and daughter with features overlapping those of Noonan syndrome, with sparse and slow-growing hair (NSLH1; 607721), Hannig et al. (2014) identified heterozygosity for a c.519G-A transition (c.519G-A, NM_007373.3) in the SHOC2 gene, resulting in a met173-to-ile (M173I) substitution at a highly conserved residue within the fourth leucine-rich repeat in the LRR domain. The mutation was not found in 6,500 asymptomatic individuals. Functional analysis in COS1 cells with constitutive knockdown of SHOC2 showed that, although wildtype SHOC2 rescued epidermal growth factor (EGF; 131530)-induced ERK1 (601795)/2 (176948) phosphorylation to the extent of endogenous SHOC2, the M173I mutant was able to restore only approximately 10% above the basal level of activity. In addition, overexpression of the M173I mutant did not lead to changes in ERK1/2 activity or in AKT (see 164730) phosphorylation. Immunoprecipitation studies in transfected 293FT cells showed that the M173I mutant failed to precipitate endogenous PP1c (see 176875) effectively, and stimulation with EGF resulted in only a mild increase in RAF1 (164760) S338 phosphorylation, compared to a dramatic increase with wildtype SHOC2. The authors concluded that the M1713 SHOC2 substitution causes loss of function in the ERK1/2 pathway. Young et al. (2018) studied the SHOC2 M173I mutation in HEK293T cells and observed increased ability to interact with MRAS (608435) and PP1 (601790) compared to wildtype SHOC2. In cotransfection assays, the M173I mutant also efficiently dephosphorylated BRAF (164757) S365 and CRAF (164760) S259. In addition, when reexpressed in SHOC2-knockout DLD1 cells, the M173I mutant decreased the higher basal levels of S365-BRAF and S259-CRAF phosphorylation as well as the impaired EGF-induced ERK pathway activation caused by SHOC2 ablation. Serum-starved DLD1 cells reexpressing SHOC2 M173I had modestly lower phosphorylated S365-BRAF and S259-CRAF levels and modestly higher phosphorylated MEK (see 176872) and RSK (see 601684) levels compared to cells expressing wildtype SHOC2, which the authors noted was consistent with RASopathy gain-of-function mutations being only weakly activating and ERK pathway activation by such mutants being difficult to detect in many experimental systems. Young et al. (2018) concluded that, like the recurrent S2G mutation (602775.0001), the M173I variant is a gain-of-function mutant that upregulates the ERK pathway during development by selectively promoting phosphatase complex formation with MRAS and PP1. (less)
Pathogenic (Aug 15, 2013)	no assertion criteria provided Method: clinical testing	Noonan-like syndrome with loose anagen hair Affected status: yes Allele origin: germline	Genetic Testing Lab, University of Kentucky College of Medicine Accession: SCV000147871.1 First in ClinVar: Apr 01, 2015 Last updated: Apr 01, 2015	Publications: PubMed (1) PubMed: 25137548

Comment:

The c.519G>A variant in the SHOC2 gene is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 173 (p.Met173Ile). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.768 (PP3). This variant has been identified as a de novo occurrence with confirmed parental relationships in 3 individuals and with unconfirmed parental relationships in 1 individual with RASopathy (PS2_VeryStrong; Invitae, GeneDx, Ambry, Genomic Medicine Lab; ClinVar SCV001573982.4, SCV000209055.14, SCV002641556.1, SCV001573024.1). This variant has been reported in more than 5 probands diagnosed with RASopathy (PS4; PMIDs: 25137548, 29907801; Invitae, GeneDx, UCSF Genomic Medicine Lab, LabCorp, Ambry; ClinVar SCV001573982.4, SCV000209055.14, SCV001573024.1, SCV000699327.2, SCV002641556.1). ERK phosphorylation assays showed that this variant decreases the ability of SHOC2 to accelerate ERK1/2 phosphorylation (PS3 not met, PMID: 25137548). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PM2_Supporting, PP3 (Specification Version 2.1, 09/17/2024)

Comment:

The SHOC2 c.519G>A (p.Met173Ile) variant has been reported in the literature in at least three individuals affected with a RASopathy. One publication described the variant occurring de novo in an affected individual and another publication described the variant in a reportedly affected father and daughter (Hannig V et al., PMID: 25137548; Motta M et al., PMID: 35348676). Additionally, this variant has been reported in the ClinVar database as a germline likely pathogenic variant by five sources and a variant of uncertain significance by three sources. Although the ClinGen RASopathy Variant Curation Expert Panel classifies this variant as a variant of uncertain significance, the classification is nearly seven years old and does not reference more current evidence. In at least one of the ClinVar entries, the submitter references internal data showing detection of the variant de novo and detection of the variant in multiple affected individuals. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to SHOC2 function. In support of this prediction, functional studies in transgenic zebrafish show the variant causes enhanced SHOC2 binding to both MRAS and PPP1CB, and the variant protein promotes increased EGF-stimulated MAPK signaling (Motta M et al., PMID: 35348676). Based on available information and the ACMG/AMP guidelines for variant interpretation and the RASopathy Variant Curation Expert Panel guidelines (Gelb BD et al., PMID: 29493581; Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.

Comment:

Variant Summary : SHOC2 c.519G>A (p.Met173Ile) results in a conservative amino acid change located in the Leucine-rich repeat (IPR001611) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250232 control chromosomes (gnomAD). c.519G>A has been reported in the literature in a father and daughter who did not have classic symptoms of NS, CFC or NS/LAH, but displayed features overlapping all three conditions, with mild clinical manifestations (Hannig_2014). The variant was also reported by a ClinVar submitter in a proband with clinical features of a RASopathy (SCV000616431.3). A different variant affecting the same amino acid (c.517A>G, p.M173V) was confirmed as de novo occurrence in one individual with Noonan-like syndrome with loose anagen hair (NS/LAH) (PMID 22670144). These data indicate that the variant may be associated with disease. Functional studies have provided somewhat contradictory conclusions regarding the mechanism of action of this variant. Hannig et al (2014) in their study demonstrated the variant protein has impaired capacity to interact with protein phosphatase 1c (PP1c), leading to insufficient activation of RAF-1 kinase and is thus unable to fully rescue ERK1/2 activity in cells depleted of endogenous SHOC2. The authors concluded that the variant causes loss of function in the ERK1/2 pathway. A more recent study (Young_2018), concluded that M173I behaves as a gain-of-function mutant that has enhanced interaction with MRAS and PP1 and rescues ERK activation by upregulating the ERK pathway in SHOC2-deficient cells. The authors describe the variant as being only weakly activating, which could perhaps correlate with presence of mild symptoms in reported patients (e.g. Hannig_2014). Two ClinVar submitters including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) (evaluation after 2014) cite the variant as uncertain significance. Based on the insufficient clinical and contradictory functional evidence outlined above, the variant was classified as uncertain significance.

Comment:

Published as paternally inherited in an individual with some features suggestive of a RASopathy, whose father was reported to have intellectual disability, a high arched palate, sparse hair, and clubbed nails, but no additional findings suggestive of a RASopathy (Hannig et al., 2014); Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate conflicting data regarding the variant's effect, with some data suggesting a gain of protein function and some data suggesting a loss of protein function (Hannig et al., 2014; Young et al., 2018). Of note, the only well-defined pathogenic variant in the SHOC2 gene known to cause a RASopathy is c.4 A>G (p.Ser2Gly), which results in altered protein localization rather than function (Cordeddu et al., 2009; Lee et al., 2011).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Classified as a variant of uncertain signficance by the ClinGen RASopathy Expert Panel (SCV000616431.1; Gelb et al., 2018); This variant is associated with the following publications: (PMID: 25137548, 29907801, 30417923, 27574535, 30050098, 33106373, 30348783)

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SHOC2 function (PMID: 25137548, 30348783). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SHOC2 protein function. ClinVar contains an entry for this variant (Variation ID: 181528). This missense change has been observed in individual(s) with clinical features of SHOC2-related conditions (PMID: 22670144, 25137548, 29907801; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 173 of the SHOC2 protein (p.Met173Ile).

Comment:

The c.519G>A (p.M173I) alteration is located in exon 2 (coding exon 1) of the SHOC2 gene. This alteration results from a G to A substitution at nucleotide position 519, causing the methionine (M) at amino acid position 173 to be replaced by an isoleucine (I). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with symptoms of Noonan-like disorder (Hannig, 2014; Ambry internal data, GeneDx pers comm, Invitae pers comm). The patient reported in Hannig, et al. (2014) had right optic nerve hypoplasia, macrocephaly, nystagmus and ptosis, speech delay, hyperactive behavior, sparse slow-growing hair, wide-spaced nipples, clubbed nails, and nonspecific findings on a brain MRI. Her height was normal. Her father was also heterozygous for this alteration and had intellectual disability, tall stature, high-arched palate, sparse hair, and clubbed nails. This amino acid position is highly conserved in available vertebrate species. Functional studies showed that the p.M173I mutant protein leads to dysregulation of the ERK1/2 pathway due to impaired capacity to interact with the catalytic subunit of protein phosphatase 1c and insufficient activation of RAF-1 kinase, suggesting loss-of-function as the mechanism of disease (Hannig, 2014). However, Young et al. (2018) found that p.M173I behaves as a gain-of-function mutant that has enhanced interaction with MRAS and PP1 and rescues ERK activation in SHOC2-deficient cells. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.	Leach NT	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29907801
SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.	Young LC	Proceedings of the National Academy of Sciences of the United States of America	2018	PMID: 30348783
A Novel SHOC2 Variant in Rasopathy.	Hannig V	Human mutation	2014	PMID: 25137548
RE(ACT)®: INTERNATIONAL CONGRESS ON RESEARCH ON RARE AND ORPHAN DISEASES.	-	Molecular syndromology	2012	PMID: 22670144
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6b6330b2-05be-48be-a7e9-3e8e77d8e63b	-	-	-	-

Text-mined citations for rs730881020 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_007373.4(SHOC2):c.519G>A (p.Met173Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs730881020 ...