ClinVar Miner

Submissions for variant NM_024649.5(BBS1):c.1339G>A (p.Ala447Thr) (rs200116631)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000638357 SCV000759855 uncertain significance Bardet-Biedl syndrome 2017-11-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 447 of the BBS1 protein (p.Ala447Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant also falls at the last nucleotide of exon 13 of the BBS1 coding sequence, which is part of the consensus splice site for this exon. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). This variant has not been reported in the literature in individuals with a BBS1-related disease. This variant is present in population databases (rs200116631, ExAC 0.05%). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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