Submissions for variant NM_031885.5(BBS2):c.72C>G (p.Tyr24Ter)

gnomAD frequency: 0.00003  dbSNP: rs121908175

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589350	SCV000699658	pathogenic	Bardet-Biedl syndrome	2017-08-10	criteria provided, single submitter	clinical testing	Variant summary: The BBS2 c.72C>G (p.Tyr24X) variant results in a premature termination codon, predicted to cause a truncated or absent BBS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 7/116822 control chromosomes at a frequency of 0.0000599, which does not exceed the estimated maximal expected allele frequency of a pathogenic BBS2 variant (0.0008452). This variant has been reported in multiple BBS patients in homozygous or compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762970	SCV000893411	pathogenic	Bardet-Biedl syndrome 2; Retinitis pigmentosa 74	2021-09-07	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000412476	SCV000924501	likely pathogenic	Bardet-Biedl syndrome 2	2018-06-15	criteria provided, single submitter	research	The heterozygous p.Tyr24Ter variant was identified by our study in the compound heterozygous state, with a VUS, in one individual with Bardet-Biedl syndrome. This variant has been identified in <0.01% (12/125738) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908175). Loss of function of the BBS2 gene is an established disease mechanism in autosomal recessive Bardet-Biedl syndrome 2, and this is a loss of function variant. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000589350	SCV000940175	pathogenic	Bardet-Biedl syndrome	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr24*) 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 (rs121908175, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 11567139, 21344540). ClinVar contains an entry for this variant (Variation ID: 4570). 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.
Blueprint Genetics	RCV001074960	SCV001240567	pathogenic	Retinal dystrophy	2017-09-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000412476	SCV004213988	pathogenic	Bardet-Biedl syndrome 2	2024-03-19	criteria provided, single submitter	clinical testing
OMIM	RCV000004832	SCV000025008	pathogenic	BARDET-BIEDL SYNDROME 2/6, DIGENIC	2001-09-21	no assertion criteria provided	literature only
Counsyl	RCV000412476	SCV000486607	pathogenic	Bardet-Biedl syndrome 2	2016-11-03	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787792	SCV000926802	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Natera, Inc.	RCV000412476	SCV001458478	pathogenic	Bardet-Biedl syndrome 2	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732529	SCV005367673	pathogenic	BBS2-related disorder	2024-07-23	no assertion criteria provided	clinical testing	The BBS2 c.72C>G variant is predicted to result in premature protein termination (p.Tyr24*). This variant has been reported in the homozygous or compound heterozygous states in individuals with Bardet-Biedl syndrome (Katsanis et al. 2001. PubMed ID: 11567139; Supplementary Data, Stone et al. 2017. PubMed ID: 28559085) and was identified in another individual with retinitis pigmentosa, although no second variant was described (Supplementary Data, Jespersgaard et al. 2019. PubMed ID: 30718709). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in BBS2 are expected to be pathogenic. This variant is interpreted as pathogenic.