Submissions for variant NM_031885.5(BBS2):c.534+1G>T

gnomAD frequency: 0.00004  dbSNP: rs773862084

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694960	SCV000823431	pathogenic	Bardet-Biedl syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 of the BBS2 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 BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). This variant is present in population databases (rs773862084, gnomAD 0.1%). Disruption of this splice site has been observed in individual(s) with Bardet-Biedl syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 553927). 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.
Fulgent Genetics, Fulgent Genetics	RCV000762968	SCV000893409	pathogenic	Bardet-Biedl syndrome 2; Retinitis pigmentosa 74	2022-02-08	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001075332	SCV001240950	likely pathogenic	Retinal dystrophy	2018-02-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001784258	SCV002022020	likely pathogenic	not provided	2021-08-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000669469	SCV002060393	pathogenic	Bardet-Biedl syndrome 2	2021-11-03	criteria provided, single submitter	clinical testing	NM_031885.3(BBS2):c.534+1G>T is a canonical splice variant classified as pathogenic in the context of Bardet-Biedl syndrome, BBS2-related. c.534+1G>T has been observed in cases with relevant disease (PMID: 24280758, 33520300, 33777945). Functional assessments of this variant are not available in the literature. c.534+1G>T has been observed in population frequency databases (gnomAD: EAS 0.14%). In summary, NM_031885.3(BBS2):c.534+1G>T is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
3billion	RCV000669469	SCV002521604	pathogenic	Bardet-Biedl syndrome 2	2022-05-22	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: 0.010%). Canonical splice site: predicted to alter splicing and result 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 at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000553927). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics	RCV000669469	SCV004213982	pathogenic	Bardet-Biedl syndrome 2	2024-03-16	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000762968	SCV005418350	pathogenic	Bardet-Biedl syndrome 2; Retinitis pigmentosa 74		criteria provided, single submitter	clinical testing	PVS1_Strong+PM2_Supporting+PM3_Supporting+PP1_Strong+PP4
Natera, Inc.	RCV000669469	SCV001458473	pathogenic	Bardet-Biedl syndrome 2	2020-09-16	no assertion criteria provided	clinical testing
Department of Pediatrics, National Cheng-Kung University Hospital	RCV000669469	SCV004042735	pathogenic	Bardet-Biedl syndrome 2		no assertion criteria provided	clinical testing	The c.534+1 G>T variant in BBS2 has been previously reported in BBS2 patients in several studies investigating syndromic ciliopathy. The variant was found in several of our patients with obesity, visual impairment, polydactyly, and renal disease, which are compatible with the BBS2 phenotype. Until now, there has not been an in vitro functional study to indicate the variant’s pathogenicity. However, it is a splice site mutation predicted to cause exon skipping, and multiple computational predictive software support its pathogenicity. In summary, the c.534+1 G>T variant in BBS2 meets the criteria of ACMG/AMP guidelines to be classified as pathogenic based on the clinical information.
Department of Traditional Chinese Medicine, Fujian Provincial Hospital	RCV000669469	SCV004046863	likely pathogenic	Bardet-Biedl syndrome 2		no assertion criteria provided	literature only	This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is a rare, autosomal recessive inherited, genetic syndrome, which involves multiple systems with diverse clinical manifestations, high disability rate and poor prognosis characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. However, in this study, not only the proband who was homozygous mutation carriers showed typical retinitis pigmentation, polydactylism, obesity, bicornuate uterus, left renal dysplasia, hypogonadism and progressive renal dysfunction, but also those heterozygous mutation carriers in the family, manifests unequal development of both kidneys, gonadal hypoplasia and dilated cardiomyopathy, which were intermediate traits. Sequencing of the RT-PCR products from the proband’s blood sample reveals a 824-nucleotide (nt) insertion exists at the junction between exons 4 and 5 of the BBS2 cDNA.