Submissions for variant NM_024649.5(BBS1):c.432+1G>A

dbSNP: rs587777829

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169013	SCV000220154	likely pathogenic	Bardet-Biedl syndrome	2014-03-12	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169013	SCV000699516	pathogenic	Bardet-Biedl syndrome	2022-03-04	criteria provided, single submitter	clinical testing	Variant summary: BBS1 c.432+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: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 247266 control chromosomes. c.432+1G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Bardet-Biedl Syndrome (example, Mykytyn_2002, Zampaglione_2020, Guardiola_2021). Additionally we have observed this variant as a compound heterozygous genotype in an individual undergoing evaluation for Bardet-Biedl Syndrome at our laboratory. 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169013	SCV001413958	pathogenic	Bardet-Biedl syndrome	2024-10-20	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the BBS1 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 BBS1 are known to be pathogenic (PMID: 12118255, 21520335, 27032803). This variant is present in population databases (rs587777829, gnomAD no frequency). Disruption of this splice site has been observed in individuals with Bardet-Biedl syndrome (PMID: 12118255; internal data). ClinVar contains an entry for this variant (Variation ID: 12145). 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.
GeneDx	RCV002225262	SCV002504200	pathogenic	not provided	2024-07-21	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12118255, 34526762, 32037395, 32349990)
Baylor Genetics	RCV000012928	SCV004217364	pathogenic	Bardet-Biedl syndrome 1	2024-01-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000012928	SCV005683589	pathogenic	Bardet-Biedl syndrome 1	2024-02-06	criteria provided, single submitter	clinical testing
OMIM	RCV000012928	SCV000033169	pathogenic	Bardet-Biedl syndrome 1	2002-08-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004742225	SCV005360031	pathogenic	BBS1-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The BBS1 c.432+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous and compound heterozygous state in patients with Bardet-Biedl syndrome (Mykytyn et al. 2002. PubMed ID: 12118255; Saeed et al. 2020. PubMed ID: 32349990). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt consensus GT splice donor sites in BBS1 are expected to be pathogenic. In summary, this variant is classified as pathogenic.