Submissions for variant NM_031885.5(BBS2):c.1237C>T (p.Arg413Ter)

gnomAD frequency: 0.00003  dbSNP: rs147030232

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411465	SCV000486380	likely pathogenic	Bardet-Biedl syndrome 2	2016-11-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762966	SCV000893407	pathogenic	Bardet-Biedl syndrome 2; Retinitis pigmentosa 74	2021-10-16	criteria provided, single submitter	clinical testing
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000411465	SCV001156386	pathogenic	Bardet-Biedl syndrome 2	2019-02-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069542	SCV001234716	pathogenic	Bardet-Biedl syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg413*) 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 (rs147030232, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 12920096, 21642631, 29588463). ClinVar contains an entry for this variant (Variation ID: 370943). 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	RCV001069542	SCV001361413	pathogenic	Bardet-Biedl syndrome	2019-08-30	criteria provided, single submitter	clinical testing	Variant summary: BBS2 c.1237C>T (p.Arg413X) 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. The variant allele was found at a frequency of 2e-05 in 251474 control chromosomes (gnomAD). c.1237C>T has been reported in the literature (including homozygous occurrences) in multiple individuals and families affected with Bardet-Biedl Syndrome (e.g. Fauser_2003, Chen_2011, Sanchez-Navarro_2018, Liu_2015). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (1x) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001571149	SCV001795568	pathogenic	not provided	2019-06-07	criteria provided, single submitter	clinical testing	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: 31960602, 30293640, 21642631, 12920096, 25525159, 21052717, 15224652)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000411465	SCV002557565	pathogenic	Bardet-Biedl syndrome 2	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bardet-Biedl syndrome 2 (MIM#615981) and retinitis pigmentosa 74 (MIM#616562). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 6 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (Decipher; PMID: 31283077). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by clinical diagnostic laboratories and has been reported as homozygous or compound heterozygous in individuals with Bardet-Biedl syndrome 2 or retinitis pigmentosa (ClinVar; PMIDs: 19797195, 21344540, 26325687, 29588463, 31960602). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV000411465	SCV004213983	pathogenic	Bardet-Biedl syndrome 2	2023-10-22	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV003889878	SCV004705058	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000411465	SCV005052037	pathogenic	Bardet-Biedl syndrome 2	2024-02-01	criteria provided, single submitter	curation
Natera, Inc.	RCV000411465	SCV001457436	pathogenic	Bardet-Biedl syndrome 2	2020-09-16	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000411465	SCV001760373	likely pathogenic	Bardet-Biedl syndrome 2		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530497	SCV004743069	pathogenic	BBS2-related disorder	2024-02-06	no assertion criteria provided	clinical testing	The BBS2 c.1237C>T variant is predicted to result in premature protein termination (p.Arg413*). This variant has previously been found in the compound heterozygous and homozygous states in individuals with autosomal recessive Bardet-Biedl syndrome and retinitis pigmentosa (Janssen et al. 2011. PubMed ID: 21052717; Dan et al. 2020. PubMed ID: 31960602; Liu et al. 2015. PubMed ID: 25611614). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. Nonsense variants in BBS2 are expected to be pathogenic. This variant is interpreted as pathogenic.