Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000578725 | SCV000681060 | uncertain significance | not provided | 2017-11-07 | criteria provided, single submitter | clinical testing | The A33D variant in the GNAS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A33D variant is observed in 5/8264 (0.06%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). The A33D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. We interpret A33D as a variant of uncertain significance. |
| Fulgent Genetics, |
RCV002491150 | SCV002781019 | uncertain significance | McCune-Albright syndrome; Pseudohypoparathyroidism type 1C; Pseudohypoparathyroidism type 1B; Pseudopseudohypoparathyroidism; Progressive osseous heteroplasia; Pituitary adenoma 3, multiple types; ACTH-independent macronodular adrenal hyperplasia 1; Pseudohypoparathyroidism type I A | 2021-12-10 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004527666 | SCV004106694 | uncertain significance | GNAS-related disorder | 2023-09-08 | criteria provided, single submitter | clinical testing | The GNAS c.98C>A variant is predicted to result in the amino acid substitution p.Ala33Asp. This variant is pre-coding in the primary transcript NM_000516.5. To our knowledge, this variant has not been reported in the literature. To our knowledge, only large deletions in this region of the gene are conclusively pathogenic for pseudohypoparathyroidism type-Ib (PHP-Ib) due to methylation defects (Turan and Bastepe. 2015. PubMed ID: 25851935). Although, in some studies single nucleotide variants (SNVs) within this region have been reported in related diseases, the pathogenicity of these variants is still uncertain (see for example in Table 3 of Long et al. 2018. PubMed ID: 30022773). This variant is reported in 0.059% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-57428418-C-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |