Submissions for variant NM_031885.5(BBS2):c.345+5G>A

gnomAD frequency: 0.00001  dbSNP: rs1430976492

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000785922	SCV000924500	uncertain significance	Bardet-Biedl syndrome 2	2018-06-15	criteria provided, single submitter	research	The heterozygous c.345+5G>A variant was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with Bardet-Biedl syndrome. This variant is located in the extended 5' splice region. This variant has been identified in <0.01% (1/15002) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377154	SCV001574406	likely pathogenic	Bardet-Biedl syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the BBS2 gene. It does not directly change the encoded amino acid sequence of the BBS2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 22773737). ClinVar contains an entry for this variant (Variation ID: 635048). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797793	SCV002041781	uncertain significance	not specified	2021-11-05	criteria provided, single submitter	clinical testing	Variant summary: BBS2 c.345+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant no significant impact on splicing. One predict the variant weakens the canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251306 control chromosomes. c.345+5G>A has been reported in the literature as a homozygous genotype in at-least one comprehensively analyzed individual affected with Bardet-Biedl Syndrome and has been subsequently reported in overlapping cohorts (example, Redin_2012, M'hamdi_2014). 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 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.