Submissions for variant NM_024649.5(BBS1):c.951+1G>A

dbSNP: rs746875134

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410778	SCV000486351	likely pathogenic	Bardet-Biedl syndrome 1	2016-05-20	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000410778	SCV001366246	pathogenic	Bardet-Biedl syndrome 1	2018-11-15	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4. This variant was detected in homozygous state.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000735921	SCV001431953	pathogenic	Bardet-Biedl syndrome	2020-08-17	criteria provided, single submitter	clinical testing	Variant summary: BBS1 c.951+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 a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251330 control chromosomes. c.951+1G>A has been reported in the literature in multiple individuals affected with features of Bardet-Biedl Syndrome (example, Fauser_2003, Redin_2012, Forsyth_2017, Komazec_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000735921	SCV001577422	pathogenic	Bardet-Biedl syndrome	2023-08-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 370919). Disruption of this splice site has been observed in individuals with Bardet-Biedl syndrome (PMID: 12920096, 27659767, 30614526). This variant is present in population databases (rs746875134, gnomAD 0.003%). This sequence change affects a donor splice site in intron 10 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).
GeneDx	RCV002248642	SCV002520317	pathogenic	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Observed with a second variant in the BBS1 gene (phase unknown) in a patient with Bardet-Biedl syndrome (Fauser et al., 2003); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30614526, 30259503, 12920096, 22773737, 27659767)
3billion	RCV000410778	SCV002572580	pathogenic	Bardet-Biedl syndrome 1	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). It is predicted to alter splicing, resulting in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000370919 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000410778	SCV004217362	pathogenic	Bardet-Biedl syndrome 1	2023-10-04	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	RCV000735921	SCV000839554	pathogenic	Bardet-Biedl syndrome	2018-09-15	no assertion criteria provided	provider interpretation