ClinVar Miner

Submissions for variant NM_024685.4(BBS10):c.1091del (p.Asn364fs) (rs727503818)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723707 SCV000202224 pathogenic not provided 2014-05-02 criteria provided, single submitter clinical testing
Counsyl RCV000169072 SCV000220239 likely pathogenic Bardet-Biedl syndrome 10 2014-04-09 criteria provided, single submitter literature only
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000169072 SCV000221174 pathogenic Bardet-Biedl syndrome 10 2014-08-04 criteria provided, single submitter clinical testing The Asn364ThrfsX5 variant in BBS10 has been reported in 1 individual with Bardet Biedl syndrome in whom it was found to be in compound heterozygosity with another frameshift variant (Muller 2010). This variant was also not identified in large population studies. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 364 and lead to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Integrated Genetics/Laboratory Corporation of America RCV000152827 SCV000699619 pathogenic Bardet-Biedl syndrome 2016-06-09 criteria provided, single submitter clinical testing Variant summary: The BBS10 c.1091delA (p.Asn364Thrfs) variant results in a premature termination codon, predicted to cause a truncated or absent BBS10 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 6/121092 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic BBS10 variant (0.0013363). It was reported in several BBS patients in either homozygosity or compound heterozygosity with a disease causing variant indicating pathogenicity. Furthermore, truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1428delC, c.1677delC). Moreover, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000169072 SCV000914602 pathogenic Bardet-Biedl syndrome 10 2018-08-15 criteria provided, single submitter clinical testing The BBS10 c.1091delA (p.Asn364ThrfsTer5) variant results in a frameshift, and is predicted to result in premature termination of the protein. Across four studies, the p.Asn364ThrfsTer5 variant has been identified in a total of four individuals with Bardet-Biedl syndrome (BBS) including in two in a homozygous state and in two in a compound heterozygous state with a second null variant (White et al. 2007; Muller et al. 2010; Chen et al. 2011; Pierrottet et al. 2014). One homozygous individual was also heterozygous for a missense variant in the BBS6 gene (Chen et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.001676 in the Ashkenazi Jewish population of the Genome Aggregation Database. Based on the evidence, the p.Asn364ThrfsTer5 variant is classified as pathogenic for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000152827 SCV000942345 pathogenic Bardet-Biedl syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the BBS10 gene (p.Asn364Thrfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 360 amino acids of the BBS10 protein. This variant is present in population databases (rs727503818, ExAC 0.009%). This variant has been observed in combination with another BBS10 variant in an individual affected with Bardet-Biedl syndrome (PMID: 20177705). ClinVar contains an entry for this variant (Variation ID: 166723). This variant disrupts the C-terminus of the BBS10 protein. Other variant(s) that disrupt this region (p.Val707*) have 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.
Laboratory of Medical Genetics, INSERM RCV000152827 SCV000839556 pathogenic Bardet-Biedl syndrome 2018-09-15 no assertion criteria provided provider interpretation

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