Submissions for variant NM_033028.5(BBS4):c.1440dup (p.Leu481fs)

gnomAD frequency: 0.00006  dbSNP: rs780269741

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237997	SCV002051353	uncertain significance	not specified	2025-01-23	criteria provided, single submitter	clinical testing	Variant summary: BBS4 c.1440dupG (p.Leu481AlafsX31) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. However, this variant is not predicted to result in NMD and there are no downstream variants with sufficient evidence for likely pathogenic/pathogenic classification. The variant allele was found at a frequency of 8e-06 in 251074 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1440dupG in individuals affected with Bardet-Biedl Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1331478). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001806822	SCV002179489	uncertain significance	Bardet-Biedl syndrome	2022-07-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu481Alafs*31) in the BBS4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acid(s) of the BBS4 protein. This variant is present in population databases (rs780269741, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BBS4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1331478). 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.
Fulgent Genetics, Fulgent Genetics	RCV005006065	SCV005633163	likely pathogenic	Bardet-Biedl syndrome 4	2024-06-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003911020	SCV004718998	likely pathogenic	BBS4-related disorder	2024-02-13	no assertion criteria provided	clinical testing	The BBS4 c.1440dupG variant is predicted to result in a frameshift and premature protein termination (p.Leu481Alafs*31). To our knowledge, this variant has not been reported in any affected individuals in the literature. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD. Frameshift variants in BBS4 are expected to be pathogenic; however, this variant is at the end of the penultimate exon, calling its clinical significance into question. This variant is interpreted as likely pathogenic.