Submissions for variant NM_024649.5(BBS1):c.436C>T (p.Arg146Ter)

gnomAD frequency: 0.00001  dbSNP: rs786204444

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169066	SCV000220230	likely pathogenic	Bardet-Biedl syndrome	2014-04-08	criteria provided, single submitter	literature only
GeneDx	RCV000627244	SCV000748235	pathogenic	not provided	2018-04-26	criteria provided, single submitter	clinical testing	The R146X variant in the BBS1 gene has been reported previously in the homozygous and compound heterozygous state in multiple individuals with Bardet-Biedl syndrome (M'hamdi et al., 2014; Muller et al., 2010; Leitch et al., 2008). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R146X variant is observed in 1/22300 (0.004%) alleles from individuals of Finnish background (Lek et al., 2016). We interpret R146X as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169066	SCV000918632	pathogenic	Bardet-Biedl syndrome	2018-09-24	criteria provided, single submitter	clinical testing	Variant summary: BBS1 c.436C>T (p.Arg146X) 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. The variant allele was found at a frequency of 8.1e-06 in 246238 control chromosomes (gnomAD). c.436C>T has been reported in the literature in multiple individuals affected with Bardet-Biedl Syndrome (Beales_2003, Fauser_2003, M'Hanmdi_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000169066	SCV000954878	pathogenic	Bardet-Biedl syndrome	2023-08-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188752). This premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 12677556, 12920096, 18327255, 20177705, 21052717). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg146*) in the BBS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS1 are known to be pathogenic (PMID: 12118255, 21520335, 27032803).
Fulgent Genetics, Fulgent Genetics	RCV001272374	SCV002810590	pathogenic	Bardet-Biedl syndrome 1	2022-02-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398862	SCV004111713	pathogenic	BBS1-related condition	2023-12-29	criteria provided, single submitter	clinical testing	The BBS1 c.436C>T variant is predicted to result in premature protein termination (p.Arg146*). This variant was reported in the homozygous and compound heterozygous states in individuals with Bardet-Biedl syndrome (Beales et al. 2003. PubMed ID: 12677556; Leitch et al. 2008. PubMed ID: 18327255; Muller et al. 2010. PubMed ID: 20177705; M'hamdi et al. 2014. PubMed ID: 23432027). This variant is reported in 0.0040% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in BBS1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV001272374	SCV004217395	pathogenic	Bardet-Biedl syndrome 1	2023-02-21	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	RCV000169066	SCV000839552	pathogenic	Bardet-Biedl syndrome	2018-09-15	no assertion criteria provided	provider interpretation
Natera, Inc.	RCV001272374	SCV001454310	pathogenic	Bardet-Biedl syndrome 1	2020-09-16	no assertion criteria provided	clinical testing