Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000414014 | SCV000491430 | likely pathogenic | not provided | 2016-02-15 | criteria provided, single submitter | clinical testing | The G343D variant in the SHH gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G343D variant was not observed in approximately 5300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G343D 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (A346V, P347L, P347R, P347Q) have been reported in the Human Gene Mutation Database in association with HPE (Stenson et al., 2014), supporting the functional importance of this region of the protein. The G343D variant is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded. |
| Invitae | RCV001861421 | SCV002152624 | uncertain significance | Holoprosencephaly 3 | 2021-10-21 | 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 372894). This variant has not been reported in the literature in individuals affected with SHH-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces glycine with aspartic acid at codon 343 of the SHH protein (p.Gly343Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. |