ClinVar Miner

Submissions for variant NM_152618.3(BBS12):c.476C>T (p.Pro159Leu)

gnomAD frequency: 0.00004  dbSNP: rs1450190654
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671341 SCV000796305 uncertain significance Bardet-Biedl syndrome 12 2017-12-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001046755 SCV001210669 likely pathogenic Bardet-Biedl syndrome 2023-12-06 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 159 of the BBS12 protein (p.Pro159Leu). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with BBS12-related conditions (PMID: 22410627, 25982971). ClinVar contains an entry for this variant (Variation ID: 555505). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BBS12 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BBS12 function (PMID: 20080638, 20498079). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics RCV001074269 SCV001239842 likely pathogenic Retinal dystrophy 2019-05-14 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003420188 SCV004109031 uncertain significance BBS12-related disorder 2023-03-09 criteria provided, single submitter clinical testing The BBS12 c.476C>T variant is predicted to result in the amino acid substitution p.Pro159Leu. This variant was reported in at least two individuals with Bardet-Biedl syndrome (Stoetzel et al. 2007. PubMed ID: 17160889; Scheidecker et al. 2015. PubMed ID: 25982971; Daniels et al. 2012. PubMed ID: 22410627; Chen et al. 2011. PubMed ID: 21642631). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-123663523-C-T). Functional studies are conflicting, one study concludes this variant as benign (Zaghloul NA et al 2010. PubMed ID: 20498079 Table S5), another study shows reduced protein interaction with BBS6, while interaction with BBS7 in unaffected (Seo et al. 2010. PubMed ID: 20080638). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics RCV000671341 SCV004211695 likely pathogenic Bardet-Biedl syndrome 12 2024-02-20 criteria provided, single submitter clinical testing
Natera, Inc. RCV000671341 SCV002082483 uncertain significance Bardet-Biedl syndrome 12 2020-10-14 no assertion criteria provided clinical testing

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