Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001048720 | SCV001212736 | uncertain significance | RASopathy | 2021-04-23 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SHOC2-related conditions. This variant is present in population databases (rs758241851, ExAC 0.02%). This sequence change replaces threonine with asparagine at codon 494 of the SHOC2 protein (p.Thr494Asn). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and asparagine. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420775 | SCV001623128 | likely benign | not specified | 2021-05-02 | criteria provided, single submitter | clinical testing | Variant summary: SHOC2 c.1481C>A (p.Thr494Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251388 control chromosomes, predominantly at a frequency of 0.00042 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17 fold of the estimated maximal expected allele frequency for a pathogenic variant in SHOC2 causing Noonan Syndrome With Loose Anagen Hair phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.1481C>A in individuals affected with Noonan Syndrome With Loose Anagen Hair and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |