ClinVar Miner

Submissions for variant NM_144596.4(TTC8):c.489G>A (p.Thr163=) (rs119103286)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000002639 SCV000245674 uncertain significance Bardet-Biedl syndrome 8 2014-12-10 criteria provided, single submitter clinical testing The p.Thr163Thr variant in TTC8 has been reported in 1 African individual with clinical features of Bardet-Biedl syndrome and was found to segregate with diseases in 2 affected relatives (Stoetzel 2005). This variant has been identified in 0.023% (2/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs119103286). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is located in the last three bases of the exon, which is part of the 5’ splice region. Computational tools predict altered splicing. However, this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Thr163Thr variant is uncertain.
Invitae RCV000203928 SCV000261521 pathogenic Bardet-Biedl syndrome 2019-12-31 criteria provided, single submitter clinical testing This sequence change affects codon 153 of the TTC8 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TTC8 protein. This variant also falls at the last nucleotide of exon 5 of the TTC8 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs119103286, ExAC 0.02%). This variant has been observed in individual(s) with Bardet Biedl syndrome (PMID: 16308660). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2530). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415339 SCV000492803 likely pathogenic Postaxial foot polydactyly; Truncal obesity; Intellectual disability, moderate 2015-07-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000002639 SCV000914655 uncertain significance Bardet-Biedl syndrome 8 2018-12-05 criteria provided, single submitter clinical testing The TTC8 c.459G>A (p.Thr153) variant is a synonymous variant predicted to abolish a splice site in exon 4. The p.Thr153= variant has been reported in two studies in which it is found in a homozygous state in four individuals affected with Bardet-Biedl Syndrome, including three siblings (Stoetzel et al. 2006; Schaefer et al. 2011). This variant is present in both sets of parents in a heterozygous state, absent from 137 control individuals and is reported at a frequency of 0.000140 in the European (non-Finnish) population of the Genome Aggregation Database (Stoetzel et al. 2006; Schaefer et al. 2011). Based on the limited evidence, the p.Thr153 variant is classified as a variant of unknown significance but suspicious for pathogenicity for Bardet-Biedl Syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Blueprint Genetics RCV001074706 SCV001240299 pathogenic Retinal dystrophy 2019-04-03 criteria provided, single submitter clinical testing
OMIM RCV000002639 SCV000022797 pathogenic Bardet-Biedl syndrome 8 2006-01-01 no assertion criteria provided literature only

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