Submissions for variant NM_031885.5(BBS2):c.646C>T (p.Arg216Ter)

gnomAD frequency: 0.00001  dbSNP: rs121908180

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668482	SCV000793094	pathogenic	Bardet-Biedl syndrome 2	2017-08-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001056084	SCV001220503	pathogenic	Bardet-Biedl syndrome	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg216*) 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 (rs121908180, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 11567139, 20120035). ClinVar contains an entry for this variant (Variation ID: 4583). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001056084	SCV001554509	pathogenic	Bardet-Biedl syndrome	2021-03-18	criteria provided, single submitter	clinical testing	Variant summary: BBS2 c.646C>T (p.Arg216X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251182 control chromosomes. c.646C>T has been reported in the literature in multiple individuals affected with Bardet-Biedl Syndrome. These data indicate that the variant is very likely to be associated with disease. Four 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV001056084	SCV003915859	pathogenic	Bardet-Biedl syndrome		criteria provided, single submitter	research
Baylor Genetics	RCV000668482	SCV004214058	pathogenic	Bardet-Biedl syndrome 2	2024-03-26	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000668482	SCV005044796	pathogenic	Bardet-Biedl syndrome 2		criteria provided, single submitter	clinical testing	The stop gained c.646C>T p.Arg216Ter variant in BBS2 gene has been reported in compound heterozygous state in individuals affected with Bardet-Biedl syndrome 2 Hjortshøj TD et al. 2010; Karmous-Benailly H et al. 2005. The p.Arg216Ter variant has allele frequency 0.001% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. The nucleotide change c.646C>T in BBS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss-of-function variants in BBS2 are known to be pathogenic Ece Solmaz A et al. 2015. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005016241	SCV005644063	pathogenic	Bardet-Biedl syndrome 2; Retinitis pigmentosa 74	2024-06-19	criteria provided, single submitter	clinical testing
OMIM	RCV000004845	SCV000025021	pathogenic	BARDET-BIEDL SYNDROME 2/6, DIGENIC	2001-09-21	no assertion criteria provided	literature only
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787791	SCV000926801	likely pathogenic	Retinal dystrophy	2018-04-01	no assertion criteria provided	research
Natera, Inc.	RCV000668482	SCV001458471	pathogenic	Bardet-Biedl syndrome 2	2020-09-16	no assertion criteria provided	clinical testing