Submissions for variant NM_031885.5(BBS2):c.823C>T (p.Arg275Ter)

gnomAD frequency: 0.00010  dbSNP: rs121908177

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000493074	SCV000338211	pathogenic	not provided	2016-01-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000004834	SCV000398065	pathogenic	Bardet-Biedl syndrome 2	2017-04-28	criteria provided, single submitter	clinical testing	The BBS2 c.823C>T (p.Arg275Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg275Ter variant has been reported in at least five studies in which it is found in at least nine patients with Bardet-Biedl syndrome including in six from four independent families in a homozygous state, in one in a compound heterozygous state, in one in a heterozygous state with a second missense variant where phase is unknown, and in one in a heterozygous state with two additional variants in the BBS1 gene (Katsanis et al. 2001; Nishimura et al. 2001; Badano et al. 2003; Chen et al. 2011; Janssen et al. 2011). The variant is also found in a heterozygous state in at least four unaffected family members (Katsanis et al. 2001; Badano et al. 2003). The p.Arg275Ter variant was absent from at least 312 control chromosomes but is reported at a frequency of 0.00076 in the European (Finnish) population of the Exome Aggregation Consortium. Based on the evidence and potential impact of stop-gained variants, the p.Arg275Ter 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.
GeneDx	RCV000493074	SCV000582400	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing	Identified in the homozygous state or with a pathogenic variant on the opposite allele in multiple unrelated patients with Bardet-Biedl syndrome referred for genetic testing at GeneDx and in the published literature (Katsanis et al., 2001; Bandano et al., 2003; Janssen et al., 2011; Olson et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11285252, 11567139, 25525159, 28502102, 28559085, 21642631, 12837689, 21052717, 30293640, 28387813, 27535533, 31980526, 31589614)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000269226	SCV000636529	pathogenic	Bardet-Biedl syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg275*) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). This variant is present in population databases (rs121908177, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 11285252, 11567139, 12837689, 21052717, 21642631). ClinVar contains an entry for this variant (Variation ID: 4572). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762967	SCV000893408	pathogenic	Bardet-Biedl syndrome 2; Retinitis pigmentosa 74	2022-01-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004834	SCV000918639	pathogenic	Bardet-Biedl syndrome 2	2018-06-25	criteria provided, single submitter	clinical testing	Variant summary: BBS2 c.823C>T (p.Arg275X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position has been classified as pathogenic by our laboratory (eg. c.1864C>T, p.Arg622X). The variant allele was found at a frequency of 0.0002 in 277510 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in BBS2 causing Bardet-Biedl Syndrome (0.0002 vs 0.00085), allowing no conclusion about variant significance. The variant, c.823C>T, has been reported in the literature in multiple individuals affected with Bardet-Biedl Syndrome (Katsanis_2001, Nishimura_2001, Badano_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000004834	SCV001194096	pathogenic	Bardet-Biedl syndrome 2	2019-12-20	criteria provided, single submitter	clinical testing	NM_031885.3(BBS2):c.823C>T(R275*) is classified as pathogenic in the context of BBS2-related Bardet-Biedl Syndrome. Sources cited for classification include the following: PMID 11567139 and 11285252. Classification of NM_031885.3(BBS2):c.823C>T(R275*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Blueprint Genetics	RCV001074104	SCV001239673	pathogenic	Retinal dystrophy	2019-01-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000493074	SCV001249675	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002466394	SCV002761950	pathogenic	Retinitis pigmentosa 74	2021-07-25	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000762967	SCV002764454	likely pathogenic	Bardet-Biedl syndrome 2; Retinitis pigmentosa 74	2020-11-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004834	SCV004213989	pathogenic	Bardet-Biedl syndrome 2	2024-03-28	criteria provided, single submitter	clinical testing
OMIM	RCV000004834	SCV000025010	pathogenic	Bardet-Biedl syndrome 2	2001-09-21	no assertion criteria provided	literature only
Natera, Inc.	RCV000004834	SCV001457440	pathogenic	Bardet-Biedl syndrome 2	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528072	SCV004104670	pathogenic	BBS2-related disorder	2024-08-06	no assertion criteria provided	clinical testing	The BBS2 c.823C>T variant is predicted to result in premature protein termination (p.Arg275*). This variant has been reported in the homozygous or compound heterozygous state in many individuals with Bardet-Biedl syndrome (see for example, Katsanis et al. 2001. PubMed ID: 11567139; Lei et al. 2017. PubMed ID: 28387813; Álvarez-Satta et al. 2017. PubMed ID: 28502102; Meyer et al. 2022. PubMed ID: 35112343). This variant is reported in 0.064% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in BBS2 are expected to be pathogenic. This variant is interpreted as pathogenic.