Submissions for variant NM_031885.5(BBS2):c.1438C>T (p.Arg480Ter)

gnomAD frequency: 0.00001  dbSNP: rs778090540

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668777	SCV000793430	pathogenic	Bardet-Biedl syndrome 2	2017-08-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000668777	SCV000915722	likely pathogenic	Bardet-Biedl syndrome 2	2019-01-09	criteria provided, single submitter	clinical testing	The BBS2 c.1438C>T (p.Arg480Ter) variant is a stop gained variant which has been reported in at least five studies in which it is found in a total of four probands with Bardet-Biedl syndrome, including one in a homozygous state and three in a compound heterozygous state (Ansley et al. 2003; Janssen et al. 2011; Xing et al. 2014; Hirano et al. 2015; Olson et al. 2019). The homozygous individual and their unaffected father also carried two variants in cis in the BBS9 gene (Xing et al. 2014). In all families, the variant was identified in at least one unaffected parent in a heterozygous state. The variant was absent from 396 controls but is reported at a frequency of 0.00012 in the East Asian population of the Exome Aggregation Consortium. However, the frequency data are based on one allele, so the variant is presumed to be rare. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Arg480Ter variant is classified as likely pathogenic for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000794157	SCV000933547	pathogenic	Bardet-Biedl syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg480*) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). This variant is present in population databases (rs778090540, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 21052717, 24608809). ClinVar contains an entry for this variant (Variation ID: 553353). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000794157	SCV001361415	pathogenic	Bardet-Biedl syndrome	2019-09-19	criteria provided, single submitter	clinical testing	Variant summary: BBS2 c.1438C>T (p.Arg480X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.4e-05 in 251458 control chromosomes (gnomAD). c.1438C>T has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Hirano_2015, Janssen_2011, Xing_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant twice as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000668777	SCV001443723	pathogenic	Bardet-Biedl syndrome 2	2019-10-23	criteria provided, single submitter	clinical testing	This nonsense variant found in exon 12 of 17 is predicted to result in loss of normal protein function. This variant has been previously reported as a compound heterozygous or homozygous change in patients with Bardet-Biedl Syndrome, including thoraco-abdominal abnormalities and congenital heart defects (PMID: 21052717, 24608809, 26325687, 30293640). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0024% (6/251,458) and thus is presumed to be rare. Based on the available evidence, the c.1438C>T (p.Arg480Ter) variant is classified as Pathogenic.
Baylor Genetics	RCV000668777	SCV004214009	pathogenic	Bardet-Biedl syndrome 2	2024-03-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000668777	SCV002089276	pathogenic	Bardet-Biedl syndrome 2	2020-11-18	no assertion criteria provided	clinical testing