Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000188353 | SCV000336775 | uncertain significance | not provided | 2015-11-09 | criteria provided, single submitter | clinical testing | |
| New York Genome Center | RCV002265675 | SCV002548647 | uncertain significance | Developmental and epileptic encephalopathy, 9 | 2021-06-23 | criteria provided, single submitter | clinical testing | The c.539C>G (p.Thr180Arg) variant identified in the PCDH19 gene substitutes a well conserved Threonine for Arginine at amino acid 180/1149 (exon1/6). This variant is found with low frequency in gnomAD(V3.1.1) (3 heterozygotes, 0 homozygotes, 0 hemizygotes; allele frequency: 2.65e-5) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.00) and Benign (REVEL; score:0.3869) to the function of the canonical transcript. The c.539C>G (p.Thr180Arg) variant is reported as a Variant of Uncertain Significance in ClinVar(VarID:206317) and to our current knowledge has not been reported in affected individuals in the literature. The p.Thr180 residue is within the second Cadherin domain of PCDH19 (UniProtKB:Q8TAB3). Given the lack of compelling evidence for its pathogenicity, the c.539C>G (p.Thr180Arg) variant identified in the PCDH19 gene of this individual is reported here as a Variant of Uncertain Significance.. |
| Invitae | RCV002265675 | SCV003490405 | uncertain significance | Developmental and epileptic encephalopathy, 9 | 2022-11-02 | 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCDH19 protein function. ClinVar contains an entry for this variant (Variation ID: 206317). This variant has not been reported in the literature in individuals affected with PCDH19-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 180 of the PCDH19 protein (p.Thr180Arg). |
| Ambry Genetics | RCV003352800 | SCV004077596 | uncertain significance | Inborn genetic diseases | 2023-07-25 | criteria provided, single submitter | clinical testing | The c.539C>G (p.T180R) alteration is located in exon 1 (coding exon 1) of the PCDH19 gene. This alteration results from a C to G substitution at nucleotide position 539, causing the threonine (T) at amino acid position 180 to be replaced by an arginine (R). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |