ClinVar Miner

Submissions for variant NM_024685.4(BBS10):c.1677C>A (p.Tyr559Ter) (rs375413604)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000477827 SCV000916670 pathogenic Bardet-Biedl syndrome 10 2018-08-23 criteria provided, single submitter clinical testing Variant summary: BBS10 c.1677C>A (p.Tyr559X) 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 4e-05 in 276592 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in BBS10 causing Bardet-Biedl Syndrome (4e-05 vs 1.30e-03), allowing no conclusion about variant significance. The variant, c.1677C>A, has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Billingsley_2010, Feuillan_2011, Knopp_2015, Ohto_2017, Wang_2016). These data indicate that the variant is 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000818478 SCV000959093 pathogenic Bardet-Biedl syndrome 2018-11-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BBS10 gene (p.Tyr559*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 165 amino acids of the BBS10 protein. This variant is present in population databases (rs375413604, ExAC 0.008%). This variant has been observed in combination with other BBS10 pathogenic variant in individuals affected with Bardet-Biedl syndrome (PMID: 20472660, 27788217, 28808579). ClinVar contains an entry for this variant (Variation ID: 417949). This variant disrupts the C-terminus of the BBS10 protein. Other variant that disrupts this region (p.Val707*) has been determined to be pathogenic (PMID: 25982971, 22773737, 27486776, 20472660). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075280 SCV001240896 pathogenic Retinal dystrophy 2017-09-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000818478 SCV001338546 pathogenic Bardet-Biedl syndrome 2020-04-24 criteria provided, single submitter clinical testing Variant summary: BBS10 c.1677C>A (p.Tyr559X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-05 in 251128 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BBS10 causing Bardet-Biedl Syndrome (4e-05 vs 0.0014). c.1677C>A has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Billingsley_2010, Feuillan_2011, Knopp_2015, Ohto_2017, Wang_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477827 SCV000536909 likely pathogenic Bardet-Biedl syndrome 10 2016-08-23 no assertion criteria provided research

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