ClinVar Miner

Submissions for variant NM_152618.3(BBS12):c.2020C>T (p.Arg674Cys) (rs759088490)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000493625 SCV000332452 uncertain significance not provided 2015-06-18 criteria provided, single submitter clinical testing
GeneDx RCV000493625 SCV000582977 likely pathogenic not provided 2015-12-09 criteria provided, single submitter clinical testing The R674C variant in the BBS12 gene has been reported previously in the homozygous state in two siblings with Bardet-Biedl syndrome. These siblings also harbored another BBS12 variant in cis with R674C as well as a heterozygous variant in BBS1 (Billingsley et al., 2010). The R674C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R674C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The R674C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Counsyl RCV000669934 SCV000794735 uncertain significance Bardet-Biedl syndrome 12 2017-10-16 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001075674 SCV001241302 likely pathogenic Retinal dystrophy 2019-03-26 criteria provided, single submitter clinical testing
Invitae RCV001089798 SCV001245293 uncertain significance Bardet-Biedl syndrome 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 674 of the BBS12 protein (p.Arg674Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs759088490, ExAC 0.01%). This variant has been observed to segregate with Bardet-Biedl syndrome in a family (PMID: 20472660). ClinVar contains an entry for this variant (Variation ID: 281596). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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