Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003062412 | SCV003440330 | likely pathogenic | Bardet-Biedl syndrome | 2023-08-16 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 366 of the BBS1 protein (p.Val366Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clincial features of Bardet-Biedl syndrome (PMID: 24611592; Invitae). ClinVar contains an entry for this variant (Variation ID: 2137160). 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 BBS1 protein function. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003062412 | SCV004029706 | pathogenic | Bardet-Biedl syndrome | 2023-07-17 | criteria provided, single submitter | clinical testing | Variant summary: BBS1 c.1097T>A (p.Val366Asp) results in a non-conservative amino acid change located in the WD40 repeat domain (Castro-Sanchez_2019) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250344 control chromosomes (gnomAD). c.1097T>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Bardet-Biedl Syndrome (e.g., Alvarez-Satta_2014, Castro-Sanchez_2015, Perea-Romero_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. In a zebrafish model, the variant resulted in a reduction in both cilia length (70% of the wild type) and number (42% of the wild type), as well as smaller eyes, shortened body axes, and other gastrulation defects (e.g., Castro-Sanchez_2019). The following publications have been ascertained in the context of this evaluation (PMID: 24611592, 26082521, 31506453, 35835773). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |