ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs786204444
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Total submissions: 10
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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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000169066 SCV000954878 pathogenic Bardet-Biedl syndrome 2025-01-23 criteria provided, single submitter clinical testing 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). 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 premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 12677556, 12920096, 18327255, 20177705, 21052717). ClinVar contains an entry for this variant (Variation ID: 188752). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001272374 SCV002810590 pathogenic Bardet-Biedl syndrome 1 2022-02-12 criteria provided, single submitter clinical testing
Baylor Genetics RCV001272374 SCV004217395 pathogenic Bardet-Biedl syndrome 1 2024-03-26 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg RCV004815258 SCV005073364 pathogenic Retinal dystrophy 2009-01-01 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
PreventionGenetics, part of Exact Sciences RCV003398862 SCV004111713 pathogenic BBS1-related disorder 2023-12-29 no assertion criteria provided 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.

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