chr10-110964877-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3PS2PS4PM2_Supporting
This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA199174/MONDO:0021060/038
Frequency
Consequence
NM_007373.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Noonan syndrome-like disorder with loose anagen hair 1 Pathogenic:3
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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. -
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RASopathy Pathogenic:2
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) -
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). 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). -
See cases Pathogenic:1
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not provided Pathogenic:1
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 (PMID: 25137548); 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 (PMID: 25137548, 30348783, 33106373, 35348676).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25137548, 29907801, 30417923, 27574535, 30050098, 33106373, 34732400, 37236975, 29493581, 36579329, 35348676, 30348783) -
Non-immune hydrops fetalis Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
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. -
not specified Uncertain:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at