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

gnomAD frequency: 0.00003  dbSNP: rs377031435

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638346	SCV000759842	pathogenic	Bardet-Biedl syndrome	2023-11-20	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. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BBS4 are known to be pathogenic (PMID: 11381270, 12016587, 20177705, 27894351). This variant is present in population databases (rs377031435, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 27208204; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000638346	SCV003801221	likely pathogenic	Bardet-Biedl syndrome	2023-01-04	criteria provided, single submitter	clinical testing	Variant summary: BBS4 c.712-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 3' acceptor site and one predicts the variant abolishes the 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251474 control chromosomes (gnomAD). c.712-1G>A has been reported in the literature in at least one homozygous individual affected with retinal disease with clinical indications of Bardet-Biedl Syndrome (Ellingford_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000778446	SCV004214089	pathogenic	Bardet-Biedl syndrome 4	2024-02-15	criteria provided, single submitter	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000225493	SCV000282590	uncertain significance	Retinal dystrophy		no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000778446	SCV001760351	likely pathogenic	Bardet-Biedl syndrome 4		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003937879	SCV004747784	pathogenic	BBS4-related disorder	2024-08-19	no assertion criteria provided	clinical testing	The BBS4 c.712-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported to be pathogenic for Bardet-Biedl syndrome (see for example, Supp. Table S5 of Ellingford et al. 2016. PubMed ID: 27208204). This variant is reported in 0.0046% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice acceptor site in BBS4 are expected to be pathogenic. This variant is interpreted as pathogenic.