Submissions for variant NM_024685.4(BBS10):c.145C>T (p.Arg49Trp)

gnomAD frequency: 0.00005  dbSNP: rs768933093

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000210662	SCV000262879	pathogenic	Inborn genetic diseases	2014-09-27	criteria provided, single submitter	clinical testing	The c.145C>T (p.R49W) alteration is located in exon 1 (coding exon 1) of the BBS10 gene. This alteration results from a C to T substitution at nucleotide position 145, causing the arginine (R) at amino acid position 49 to be replaced by a tryptophan (W). The alteration is not observed in healthy cohorts: Based on data from the NHLBI Exome Sequencing Project (ESP), the BBS10 c.145C>T alteration was not observed among 6,147 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). IF USED, PULL THESE INTO REFERENCES: Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The amino acid change has been observed in affected individuals: This missense change has been reported both in homozygous and compound heterozygous form in 8 families with BBS (Stoetzel, 2006; Chen, 2011; Imhoff, 2011; Deveault, 2011). The altered amino acid is conserved throughout evolution: The p.R49 amino acid is completely conserved in available vertebrate species. The alteration is predicted deleterious by in silico models: The p.R49W alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV000576728	SCV000381160	pathogenic	Bardet-Biedl syndrome 10	2017-04-28	criteria provided, single submitter	clinical testing	The BBS10 c.145C>T (p.Arg49Trp) missense variant has been reported in nine studies in which it is found in at least 15 patients with Bardet-Biedl syndrome, including in four in a homozygous state and in 11 in a compound heterozygous state (Stoetzel et al. 2006; Hjortshøj et al. 2010; Muller et al. 2010; Bennouna-Greene et al. 2011; Chen et al. 2011; Imhoff et al. 2011; Schaefer et al. 2011; Lindstrand et al. 2014; Scheidecker et al. 2015). The p.Arg49Trp variant was absent from 192 control chromosomes and is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated that the p.Arg49Trp variant was a null allele and failed to rescue morphant phenotypes seen in zebrafish embryos in which translation of the BBS10 protein was suppressed (Zaghloul et al. 2010). Based on the collective evidence, the p.Arg49Trp variant is considered to be pathogenic for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626963	SCV000747666	pathogenic	Retinal dystrophy; Macular degeneration; Postaxial hand polydactyly; Intellectual disability; Foot polydactyly; High-frequency hearing impairment	2017-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000576728	SCV000893986	pathogenic	Bardet-Biedl syndrome 10	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000799037	SCV000938684	pathogenic	Bardet-Biedl syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 49 of the BBS10 protein (p.Arg49Trp). This variant is present in population databases (rs768933093, gnomAD 0.01%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 16582908, 20472660, 22410627, 25982971). ClinVar contains an entry for this variant (Variation ID: 225010). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BBS10 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BBS10 function (PMID: 20498079). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075496	SCV001241120	pathogenic	Retinal dystrophy	2018-11-08	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001291592	SCV001480137	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001291592	SCV001747656	pathogenic	not provided	2021-05-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000576728	SCV002022015	likely pathogenic	Bardet-Biedl syndrome 10	2020-04-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001291592	SCV002538814	pathogenic	not provided	2022-06-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Zaghloul et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30767287, 24746959, 20498079, 25982971, 16582908, 20472660, 22410627, 20080638, 20120035, 21344540, 30577886, 32686083, 33138063, 34426522)
PreventionGenetics, part of Exact Sciences	RCV003407735	SCV004116132	pathogenic	BBS10-related condition	2023-06-01	criteria provided, single submitter	clinical testing	The BBS10 c.145C>T variant is predicted to result in the amino acid substitution p.Arg49Trp. This variant was reported in the homozygous or compound heterozygous state in multiple individuals with Bardet-Biedl syndrome (Stoetzel et al. 2006. PubMed ID: 16582908; Chen et al. 2011. PubMed ID: 21642631; Scheidecker et al. 2015. PubMed ID: 25982971; Jeziorny et al. 2020. PubMed ID: 33138063). Functional studies in a zebrafish model showed that the p.Arg49Trp substitution could impact normal protein function (Zaghloul et al. 2010. PubMed ID: 20498079, Supplementary Table 4). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-76741994-G-A). This variant is interpreted as pathogenic.
Baylor Genetics	RCV000576728	SCV004217408	pathogenic	Bardet-Biedl syndrome 10	2023-10-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000576728	SCV000678121	pathogenic	Bardet-Biedl syndrome 10	2017-01-24	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000576728	SCV001462858	pathogenic	Bardet-Biedl syndrome 10	2020-09-16	no assertion criteria provided	clinical testing
Advanced Center For Translational And Genetic Medicine, Ann & Robert H. Lurie Children's Hospital Of Chicago	RCV003228914	SCV003926578	likely pathogenic	Bardet-Biedl syndrome 1	2023-05-10	no assertion criteria provided	research