ClinVar Miner

Submissions for variant NM_007373.3(SHOC2):c.519G>A (p.Met173Ile) (rs730881020)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000523270 SCV000616431 uncertain significance Rasopathy 2017-04-03 reviewed by expert panel curation The c.519G>A (p.Met173Ile) variant in the SHOC2 gene has been observed in a proband with clinical features of a RASopathy (PS4 not met; GeneDx GTR Lab ID:26957 ClinVar SCV000209055.10). This variant was absent from large population studies (PM2; ExAC, In vitro functional studies provide some evidence that the p.Met173Ile variant may impact protein function (PS3 not met; PMID: 25137548). In summary, the clinical significance of the p.Met173Ile variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2.
GeneDx RCV000586119 SCV000209055 uncertain significance not provided 2019-01-14 criteria provided, single submitter clinical testing The M173I variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Server reports M173I was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Although M173I is a conservative amino acid substitution as both Methionine and Isoleucine are non-polar residues, Methionine is highly conserved at this position across species. The only mutation published to date in the SHOC2 gene is the S2G mutation. In silico algorithms are inconsistent in predicting the effect of M173I. Therefore, based on the currently available information, it is unclear whether M173I is a disease-causing mutation or a rare benign variant. The variant is found in NOONAN panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001030821 SCV000699327 uncertain significance not specified 2020-04-02 criteria provided, single submitter clinical testing 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.
Ambry Genetics RCV001266650 SCV001444826 uncertain significance Inborn genetic diseases 2019-08-14 criteria provided, single submitter clinical testing
Genomic Medicine Lab, University of California San Francisco RCV001376015 SCV001573024 likely pathogenic Non-immune hydrops fetalis 2020-01-09 criteria provided, single submitter clinical testing
Invitae RCV000523270 SCV001573982 likely pathogenic Rasopathy 2020-06-03 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 173 of the SHOC2 protein (p.Met173Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of SHOC2-related disease (PMID: 25137548, 29907801, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 181528). This variant has been reported to have conflicting or insufficient data to determine the effect on SHOC2 protein function (PMID: 25137548, 30348783). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genetic Testing Lab, University of Kentucky College of Medicine RCV000169685 SCV000147871 pathogenic Noonan syndrome-like disorder with loose anagen hair 1 2013-08-15 no assertion criteria provided clinical testing
OMIM RCV000169685 SCV001424913 pathogenic Noonan syndrome-like disorder with loose anagen hair 1 2014-11-01 no assertion criteria provided literature only

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