ClinVar Miner

Submissions for variant NM_024649.5(BBS1):c.1126_1130CTTTG[1] (p.Cys377fs) (rs786204701)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169515 SCV000220985 likely pathogenic Bardet-Biedl syndrome 2014-12-23 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169515 SCV000918635 likely pathogenic Bardet-Biedl syndrome 2018-08-06 criteria provided, single submitter clinical testing Variant summary: BBS1 c.1131_1135delCTTTG (p.Cys377TrpfsX36) 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. One truncation downstream of this position has been classified as pathogenic by our laboratory (c.1645G>T, p.Glu549X). The variant allele was found at a frequency of 8.1e-06 in 246256 control chromosomes (gnomAD). The variant, c.1131_1135delCTTTG, has been reported in the literature in an individual affected with Bardet-Biedl Syndrome (Mykytyn_2003) but also in patients with non-syndromic retinitis pigmentosa and Leber congenital amaurosis (Estrada-Cuzcano_2012, Haer-Wigman_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx RCV001008111 SCV001167861 pathogenic not provided 2018-06-08 criteria provided, single submitter clinical testing The c.1131_1135delCTTTG variant in the BBS1 gene has been reported previously using alternate nomenclature (c.1130_1134del) in association with autosomal recessive Bardet-Biedl syndrome (Mykytyn et al., 2003; Estrada-Cuzcano et al., 2012). The c.1131_1135delCTTTG variant causes a frameshift starting with codon Cysteine 377, changes this amino acid to a Tryptophan residue, and creates a premature Stop codon at position 36 of the new reading frame, denoted p.Cys377TrpfsX36. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1131_1135delCTTTG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1131_1135delCTTTG as a pathogenic variant.

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