ClinVar Miner

Submissions for variant NM_031885.4(BBS2):c.1438C>T (p.Arg480Ter) (rs778090540)

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Total submissions: 4
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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 Clinical Services Laboratory,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 2018-12-19 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. This variant is present in population databases (rs778090540, ExAC 0.01%). This variant has been observed in individuals affected with Bardet-Biedl syndrome (PMID: 21052717, 24608809). ClinVar contains an entry for this variant (Variation ID: 553353). Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.

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