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

gnomAD frequency: 0.00002  dbSNP: rs759088490

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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.
Ambry Genetics	RCV002518825	SCV003581531	uncertain significance	Inborn genetic diseases	2021-10-27	criteria provided, single submitter	clinical testing	The c.2020C>T (p.R674C) alteration is located in exon 2 (coding exon 1) of the BBS12 gene. This alteration results from a C to T substitution at nucleotide position 2020, causing the arginine (R) at amino acid position 674 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.