Submissions for variant NM_031885.5(BBS2):c.1885G>A (p.Glu629Lys)

gnomAD frequency: 0.00004  dbSNP: rs746505864

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665367	SCV000789478	uncertain significance	Bardet-Biedl syndrome 2	2017-02-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001037054	SCV001200449	uncertain significance	Bardet-Biedl syndrome	2022-05-25	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 629 of the BBS2 protein (p.Glu629Lys). This variant is present in population databases (rs746505864, gnomAD 0.008%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 20120035). ClinVar contains an entry for this variant (Variation ID: 550587). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271550	SCV002555769	uncertain significance	not specified	2022-06-08	criteria provided, single submitter	clinical testing	Variant summary: BBS2 c.1885G>A (p.Glu629Lys) results in a conservative amino acid change located in the Ciliary BBSome complex subunit 2, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251448 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1885G>A has been reported in the literature in one individual affected with Bardet-Biedl Syndrome who also carries two BBS10 pathogenic variants. This report does not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000665367	SCV001457431	uncertain significance	Bardet-Biedl syndrome 2	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544927	SCV004788235	uncertain significance	BBS2-related disorder	2024-06-11	no assertion criteria provided	clinical testing	The BBS2 c.1885G>A variant is predicted to result in the amino acid substitution p.Glu629Lys. This variant has been reported in an individual with Bardet-Biedl syndrome; however, this individual also has two protein-truncating variants in BBS10 (Hjortshøj et al. 2010. PubMed ID: 20120035). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.