ClinVar Genomic variation as it relates to human health

Variant summary: BBS10 c.1677C>A (p.Tyr559X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-05 in 251128 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BBS10 causing Bardet-Biedl Syndrome (4e-05 vs 0.0014). c.1677C>A has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Billingsley_2010, Feuillan_2011, Knopp_2015, Ohto_2017, Wang_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 165 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Reported as pathogenic in ClinVar but additional evidence is not available (ClinVar SCV000916670.1; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30029678, 28808579, 27788217, 26003401, 21642631, 20472660, 25366773)

This sequence change creates a premature translational stop signal (p.Tyr559*) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 165 amino acid(s) of the BBS10 protein. This variant is present in population databases (rs375413604, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 20472660, 27788217, 28808579). ClinVar contains an entry for this variant (Variation ID: 417949). This variant disrupts a region of the BBS10 protein in which other variant(s) (p.Val707*) have been determined to be pathogenic (PMID: 20472660, 22773737, 25982971, 27486776). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The BBS10 c.1677C>A variant is predicted to result in premature protein termination (p.Tyr559*). This variant has been reported in patients with Bardet-Biedl syndrome and retinal disorders (Billingsley et al. 2010. PubMed ID: 20472660; Wang et al. 2016. PubMed ID: 27788217; Ohto et al. 2017. PubMed ID: 28808579). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in BBS10 are expected to be pathogenic. This variant is interpreted as pathogenic.