ClinVar Miner

Submissions for variant NM_033028.5(BBS4):c.712-1G>A (rs377031435)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000638346 SCV000759842 pathogenic Bardet-Biedl syndrome 2017-12-13 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10 of the BBS4 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs377031435, ExAC 0.001%). This variant has been reported either as homozygous or on the opposite chromosome (in trans) from a pathogenic BBS4 variant in individuals affected with Bardet-Biedl syndrome (PMID: 27208204, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 236484). 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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BBS4 are known to be pathogenic (PMID: 11381270). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000778446 SCV000914694 uncertain significance Bardet-Biedl syndrome 4 2017-09-07 criteria provided, single submitter clinical testing The BBS4 c.712-1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.712-1G>A variant has been identified in one study in which it was found in a homozygous state in one individual with Bardet-Biedl syndrome (Ellingford et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000040 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the limited evidence and the potential impact of splice acceptor variants, the c.712-1G>A variant is classified as a variant of unknown significance but suspicious for pathogenicity for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000225493 SCV000282590 uncertain significance Retinal dystrophy no assertion criteria provided clinical testing

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