ClinVar Miner

Submissions for variant NM_031885.4(BBS2):c.175C>T (p.Gln59Ter) (rs121908176)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000587533 SCV000699654 pathogenic Bardet-Biedl syndrome 2019-01-31 criteria provided, single submitter clinical testing Variant summary: BBS2 c.175C>T (p.Gln59X) 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 (eg. c.814C>T (p.Arg272X), c.823C>T (p.Arg275X), and c.1864C>T (p.Arg622X)). The variant allele was found at a frequency of 2.4e-05 in 246604 control chromosomes (gnomAD and publications). c.175C>T has been reported in the literature in individuals affected with features of Bardet-Biedl Syndrome (Katsanis_2001, Fitzgerald_2015). Katsanis_2001 proposed that this syndrome may not be a single-gene recessive disease but a complex trait requiring three mutant alleles to manifest the phenotype because an affected patient from one family carried triallelic variants BBS2 Q59X and Y24X in compound heterozygosity and BBS6 Q147X, while a sibling with the same biallelic variants in BBS2 without the BBS6 variant and father with BBS2 Q59X and BBS6 Q147X were healthy. Another publication, Abu-Safieh_2012, using a cohort of 29 BBS families was not able to support this triallelic model, arguing in favor of straightforward autosomal recessive BBS in most cases. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000587533 SCV000955325 pathogenic Bardet-Biedl syndrome 2019-11-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln59*) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121908176, ExAC 0.002%). This variant has been observed in several individuals affected with Bardet-Biedl syndrome (PMID: 11567139, 27659767). ClinVar contains an entry for this variant (Variation ID: 4571). Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004833 SCV000025009 pathogenic Bardet-Biedl syndrome 2 2001-09-21 no assertion criteria provided literature only
Counsyl RCV000004833 SCV000793615 pathogenic Bardet-Biedl syndrome 2 2017-08-25 no assertion criteria provided clinical testing

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