Submissions for variant NM_024649.5(BBS1):c.479G>A (p.Arg160Gln)

gnomAD frequency: 0.00003  dbSNP: rs376894444

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411434	SCV000485484	likely pathogenic	Bardet-Biedl syndrome 1	2015-12-23	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074216	SCV001239789	pathogenic	Retinal dystrophy	2019-04-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092069	SCV001248422	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387773	SCV001588488	pathogenic	Bardet-Biedl syndrome	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 160 of the BBS1 protein (p.Arg160Gln). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs376894444, gnomAD 0.03%). This missense change has been observed in individuals with Bardet-Biedl syndrome or nonsyndromic retinitis pigmentosa (PMID: 15770229, 21520335, 26261414). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 370228). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BBS1 protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
3billion, Medical Genetics	RCV000411434	SCV002058611	pathogenic	Bardet-Biedl syndrome 1	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000370228, PMID:26261414, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21520335, PS3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000028, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000504813	SCV002765129	pathogenic	Retinitis pigmentosa	2022-12-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000411434	SCV002783762	pathogenic	Bardet-Biedl syndrome 1	2024-02-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000411434	SCV004217394	pathogenic	Bardet-Biedl syndrome 1	2023-12-05	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074216	SCV005069205	pathogenic	Retinal dystrophy	2012-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001092069	SCV005202124	pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	RNA studies demonstrate a damaging effect through aberrant splicing (PMID: 21520335); In silico analysis supports that this missense variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34426522, 34758253, 26261414, 31456290, 15770229, 21520335, 34940782, 32531858, 35886001)
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504813	SCV000598858	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000504813	SCV001160903	pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV000411434	SCV001760274	likely pathogenic	Bardet-Biedl syndrome 1		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001092069	SCV001952172	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001092069	SCV001969377	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000411434	SCV002094727	pathogenic	Bardet-Biedl syndrome 1	2020-03-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003922662	SCV004754752	likely pathogenic	BBS1-related disorder	2024-08-06	no assertion criteria provided	clinical testing	The BBS1 c.479G>A variant is predicted to result in the amino acid substitution p.Arg160Gln. This variant has been reported in patients with retinitis pigmentosa or milder form of Bardet-Biedl syndrome. This variant is highly prevalent in patients of Arab-Muslim origin (Sharon and Banin. 2015. PubMed ID: 26261414; Hichri et al. 2005. PubMed ID: 15770229; Schmid et al. 2011. PubMed ID: 21520335; Hjortshøj et al. 2010. PubMed ID: 20120035). RT-PCR analysis indicated that this variant results in aberrant splicing. U1snRNA -mediated therapeutic approach to correct the splice defect in patient derived cell lines significantly increased correctly spliced BBS1 transcripts, which would suggest a high potential for gene therapy (Schmid et al. 2011. PubMed ID: 21520335). This variant is reported in 0.031% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic.