Submissions for variant NM_152618.3(BBS12):c.2023C>T (p.Arg675Ter)

gnomAD frequency: 0.00001  dbSNP: rs752202089

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000670073	SCV000447429	likely pathogenic	Bardet-Biedl syndrome 12	2017-04-28	criteria provided, single submitter	clinical testing	The BBS12 c.2023C>T (p.Arg675Ter) stop-gained variant has been reported in two studies in a total of three individuals, either with Bardet-Biedl syndrome (BBS) or suspected to have BBS, in a compound heterozygous state (Dulfer et al. 2010; Chen et al. 2011). Of these individuals, two were siblings who also had a heterozygous frameshift variant in the BBS10 gene. In this family, the father was heterozygous for the BBS12 p.Arg675Ter variant and the mother was heterozygous for the other variants. The other individual who had the p.Arg675Ter variant in a compound heterozygous state also had a heterozygous missense variant in the BBS1 gene. The p.Arg675Ter variant was absent from 288 controls but is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium, however this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence and due to potential impact of stop-gained variants, the p.Arg675Ter variant is classified as likely pathogenic for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000302878	SCV000759859	pathogenic	Bardet-Biedl syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg675*) in the BBS12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 36 amino acid(s) of the BBS12 protein. This variant is present in population databases (rs752202089, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 20827784, 21642631). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 347505). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000670073	SCV000894332	pathogenic	Bardet-Biedl syndrome 12	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091376	SCV001247391	pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001091376	SCV001755374	likely pathogenic	not provided	2021-07-10	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000670073	SCV004048011	likely pathogenic	Bardet-Biedl syndrome 12		criteria provided, single submitter	clinical testing	The stop gain variant c.2023C>T (p.Arg675Ter) in the BBS12 gene has been reported previously in a compound heterozygous state in patients affected with Bardet–Biedl Syndrome. Two of the patients also had a heterozygous frameshift variant in the BBS10 gene along with the BBS12 variants (Dulfer E. et al., 2010). This variant is reported with the allele frequency (0.0008%) in the gnomAD Exomes and novel in 1000 genome database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic
PreventionGenetics, part of Exact Sciences	RCV003418071	SCV004114122	pathogenic	BBS12-related disorder	2023-06-12	criteria provided, single submitter	clinical testing	The BBS12 c.2023C>T variant is predicted to result in premature protein termination (p.Arg675*). This variant has been reported to be causative for Bardet-Biedl syndrome (Dulfer. 2010. PubMed ID: 20827784; Mary et al. 2019. PubMed ID: 30614526). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-123665070-C-T). Nonsense variants in BBS12 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV000670073	SCV004211662	pathogenic	Bardet-Biedl syndrome 12	2024-03-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000670073	SCV000794888	pathogenic	Bardet-Biedl syndrome 12	2017-10-18	no assertion criteria provided	clinical testing
Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	RCV000302878	SCV000839577	pathogenic	Bardet-Biedl syndrome	2018-09-15	no assertion criteria provided	provider interpretation
Natera, Inc.	RCV000670073	SCV001462026	pathogenic	Bardet-Biedl syndrome 12	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001091376	SCV001952171	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001091376	SCV001971445	pathogenic	not provided		no assertion criteria provided	clinical testing