ClinVar Genomic variation as it relates to human health

NM_024685.3(BBS10):c.1736A>G(K579R) is a missense variant classified as a variant of uncertain significance in the context of Bardet-Biedl syndrome. K579R has been observed in cases with relevant disease (PMID: 16582908, 24488770). Functional assessments of this variant are available in the literature (PMID: 20498079). K579R has been observed in population frequency databases (gnomAD: AFR 0.46%). In summary, there is insufficient evidence to classify NM_024685.3(BBS10):c.1736A>G(K579R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

Variant summary: BBS10 c.1736A>G (p.Lys579Arg) results in a conservative amino acid change located in the Intermediate domain (Stoetzel_NatGen_2006) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 120630 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BBS10 causing Bardet-Biedl Syndrome (0.00052 vs 0.0013), allowing no conclusion about variant significance. c.1736A>G has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Stoetzel_NatGen_2006). This report does not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Published functional studies demonstrate a damaging effect, specifically, in vivo complementation analysis in Zebrafish demonstrates significant difference from wild type, and the authors predict K579R is a null allele (Zaghloul et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in the homozgyous state in a middle eastern patient with Bardet-Biedl syndrome who also harbored another BBS10 homozygous variant, that the authors felt was more likely to be causal (Stoetzel et al., 2006); This variant is associated with the following publications: (PMID: 22995991, 20498079, 16582908, 24488770)

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.