Submissions for variant NM_033028.5(BBS4):c.1541_1551del (p.Glu514fs)

gnomAD frequency: 0.00011  dbSNP: rs748758201

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV001199437	SCV001162420	pathogenic	Retinitis pigmentosa	2020-01-09	criteria provided, single submitter	research
Invitae	RCV001236156	SCV001408869	uncertain significance	Bardet-Biedl syndrome	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu514Glyfs*7) in the BBS4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the BBS4 protein. This variant is present in population databases (rs748758201, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with inherited retinal degeneration (PMID: 32531858). ClinVar contains an entry for this variant (Variation ID: 813021). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	RCV002222654	SCV002500820	uncertain significance	not specified	2022-03-31	criteria provided, single submitter	clinical testing	Variant summary: BBS4 c.1541_1551del11 (p.Glu514GlyfsX7) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.0001 in 242404 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BBS4 causing Bardet-Biedl Syndrome (0.0001 vs 0.00069), allowing no conclusion about variant significance. Elongations of the protein have not been associated with Bardet-Biedl Syndrome in HGMD. c.1541_1551del11 has been reported in the literature in an individual affected with inherited retinal degeneration, however this individual did not have a second pathogenic variant in this gene (example: Weisschuh_2020). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.