ClinVar Miner

Submissions for variant NM_031885.5(BBS2):c.685T>C (p.Tyr229His) (rs778543585)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV001005003 SCV001164564 likely pathogenic Retinitis pigmentosa 74 2018-12-03 criteria provided, single submitter research The heterozygous p.Tyr229His variant in BBS2 was identified by our study in the compound heterozygous state, with a VUS, in one individual with retinitis pigmentosa. Trio exome analysis showed this variant to be de novo. The p.Tyr229His variant in BBS2 has not been previously reported in individuals with retinitis pigmentosa but has been identified in 0.002527% (7/277022) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs778543585). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PS2 (Richards 2015).
Invitae RCV001061887 SCV001226647 uncertain significance Bardet-Biedl syndrome 2019-09-26 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 229 of the BBS2 protein (p.Tyr229His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs778543585, ExAC 0.003%). This variant has not been reported in the literature in individuals with BBS2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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