Submissions for variant NM_033028.5(BBS4):c.1414A>G (p.Met472Val)

gnomAD frequency: 0.00034  dbSNP: rs2277596

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085941	SCV000253634	likely benign	Bardet-Biedl syndrome	2025-01-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000246726	SCV000315045	likely benign	not specified		criteria provided, single submitter	clinical testing
Mendelics	RCV000490439	SCV001139651	benign	Bardet-Biedl syndrome 4	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000490439	SCV001277067	uncertain significance	Bardet-Biedl syndrome 4	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000132689	SCV001986317	uncertain significance	not provided	2019-10-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect, as a zebrafish embryo assay suggests a null mutation (Zaghloul et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in two individuals with nephronophthisis-related ciliopathy, however no second BBS4 variant was identified (Kang et al., 2016); Observed in mother and daughter with Bardet-Biedl syndrome who were both also homozygous for a variant in the BBS1 gene (Beales et al., 2003); This variant is associated with the following publications: (PMID: 15224652, 20498079, 12677556, 26260382, 27491411, 23142271, 12872256)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000246726	SCV005202682	likely benign	not specified	2024-07-30	criteria provided, single submitter	clinical testing	Variant summary: BBS4 c.1414A>G (p.Met472Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00067 in 251306 control chromosomes, predominantly at a frequency of 0.0079 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BBS4 causing Bardet-Biedl Syndrome phenotype (0.00069). Although c.1414A>G has been reported in the literature, no penetrant association of this variant has been reported in individuals affected with Bardet-Biedl Syndrome (example, Beales_2003). These report(s) do 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. The following publication has been ascertained in the context of this evaluation (PMID: 12677556). ClinVar contains an entry for this variant (Variation ID: 143161). Based on the evidence outlined above, the variant was classified as likely benign.
Department of Ophthalmology and Visual Sciences Kyoto University	RCV000132689	SCV000172642	probable-non-pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Likely benign.
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490439	SCV000267222	likely pathogenic	Bardet-Biedl syndrome 4	2016-03-18	flagged submission	reference population