ClinVar Miner

Submissions for variant NM_024649.5(BBS1):c.1553T>C (p.Leu518Pro)

gnomAD frequency: 0.00001  dbSNP: rs121917778
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000012930 SCV000807218 likely pathogenic Bardet-Biedl syndrome 1 criteria provided, single submitter clinical testing
Invitae RCV001055313 SCV001219700 pathogenic Bardet-Biedl syndrome 2023-11-04 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 518 of the BBS1 protein (p.Leu518Pro). This variant is present in population databases (rs121917778, gnomAD 0.003%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 12524598, 12920096). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12147). 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 not expected to disrupt BBS1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075155 SCV001240767 pathogenic Retinal dystrophy 2018-10-05 criteria provided, single submitter clinical testing
GeneDx RCV001753415 SCV001986115 uncertain significance not provided 2019-12-31 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed multiple times with a pathogenic variant (M390R) in unrelated patients with BBS in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Mykytyn et al., 2003; Fauser et al., 2003); This variant is associated with the following publications: (PMID: 25326635, 12524598, 12920096, 21463199, 17065520)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001055313 SCV002572146 likely pathogenic Bardet-Biedl syndrome 2022-08-18 criteria provided, single submitter clinical testing Variant summary: BBS1 c.1553T>C (p.Leu518Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251494 control chromosomes (gnomAD). c.1553T>C has been reported in the literature in multiple bi-allelic individuals (with p.M390R) affected with Bardet-Biedl Syndrome (examples: Mykytyn_2003, Fauser_2003, Azari_2006, and Haer-Wigman_2017). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM RCV000012930 SCV000033171 pathogenic Bardet-Biedl syndrome 1 2003-02-01 no assertion criteria provided literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000012930 SCV000804597 uncertain significance Bardet-Biedl syndrome 1 2016-09-01 no assertion criteria provided clinical testing

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