Submissions for variant NM_024685.4(BBS10):c.271dup (p.Cys91fs)

dbSNP: rs549625604

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168127	SCV000218785	pathogenic	Bardet-Biedl syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys91Leufs*5) in the BBS10 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 633 amino acid(s) of the BBS10 protein. This variant is present in population databases (rs549625604, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 16582908, 20805367, 27385962). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1328). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000487323	SCV000331663	pathogenic	not provided	2016-02-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000001391	SCV000381157	pathogenic	Bardet-Biedl syndrome 10	2017-04-27	criteria provided, single submitter	clinical testing	The BBS10 c.271dupT (p.Cys91LeufsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Cys91LeufsTer5 is well-documented as a common founder mutation in several ethnic groups (Suspitsin et al. 2016). Stoetzel et al. (2006) sequenced 311 families with Bardet-Biedl syndrome (BBS) and found the p.Cys91LeufsTer5 variant in 18 patients in a homozygous state, 13 in a compound heterozygous state, and five in a heterozygous state, accounting for 46% of variants detected. BBS is known to follow a complex inheritance pattern; several individuals were found in this study who also carried a third variant in one of the other genes known to be associated with BBS. The p.Cys91LeufsTer5 variant has also been identified in a homozygous state in affected individuals from two families, one of Indian descent and one of Northern European descent; in a compound heterozygous state in a 20 year old woman with BBS; and in three fetal cases (Putoux et al. 2010; Lindstrand et al. 2014; Sathya Priya et al. 2015). Control data are unavailable for this variant which is reported at a frequency of 0.00121 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Cys91LeufsTer5 variant is classified as pathogenic for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000487323	SCV000568844	pathogenic	not provided	2022-01-18	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 633 amino acids are replaced with 4 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 20177705, 21463199, 27245532, 29974258, 24746959, 24400638, 16582908, 20472660, 25988237, 20805367, 28143435, 30614526, 30718709, 30947698, 28041643, 30312873, 29096039, 30767287, 32349990, 32581362, 24077912)
Genetic Services Laboratory, University of Chicago	RCV000001391	SCV000593594	pathogenic	Bardet-Biedl syndrome 10	2016-03-15	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000487323	SCV000612485	pathogenic	not provided	2015-09-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000168127	SCV000699624	pathogenic	Bardet-Biedl syndrome	2017-05-14	criteria provided, single submitter	clinical testing	Variant summary: The BBS10 c.271dupT (p.Cys91Leufs) variant results in a premature termination codon, predicted to cause a truncated or absent BBS10 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 81/119742 control chromosomes at a frequency of 0.0006765, which does not exceed the estimated maximal expected allele frequency of a pathogenic BBS10 variant (0.0013363). The variant of interest has been reported in multiple affected homozygous and compound heterozygous individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics	RCV000623309	SCV000740720	pathogenic	Inborn genetic diseases	2022-01-12	criteria provided, single submitter	clinical testing	The c.271dupT (p.C91Lfs*5) alteration, located in coding exon 2 of the BBS10 gene, consists of a duplication of T at position 271, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration occurs at the 3' terminus of the BBS10 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts 88% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This mutation has been reported both in homozygous and compound heterozygous form in 58 families with Bardet-Biedl syndrome (Stoetzel, 2006; Chen, 2011; Imhoff, 2011; Deveault, 2011; Janssen, 2011). Haplotyping data suggested that this is an ancient founder mutation found in several ethnic groups (Stoetzel, 2006). Based on the available evidence, this alteration is classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000709625	SCV000744062	pathogenic	Bardet-Biedl syndrome 1	2016-01-27	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000709625	SCV000745512	pathogenic	Bardet-Biedl syndrome 1	2017-05-31	criteria provided, single submitter	clinical testing
MAGI'S LAB - Medical Genetics Laboratory, MAGI GROUP	RCV000168127	SCV000897985	pathogenic	Bardet-Biedl syndrome	2018-10-01	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	RCV000001391	SCV000902271	pathogenic	Bardet-Biedl syndrome 10		criteria provided, single submitter	clinical testing	Sanger sequencing showed a homozygous sequence variant in BBS10 gene resulting in frameshift. It is predicted as pathogenic by MutationTaster. This variant is classified as pathogenic which shows strong evidence of pathogenicity according to ACMG guidelines (Richards et al., 2015). Parents were heterozygous for the same variation.
Myriad Genetics, Inc.	RCV000001391	SCV001194069	pathogenic	Bardet-Biedl syndrome 10	2019-11-12	criteria provided, single submitter	clinical testing	NM_024685.3(BBS10):c.271dupT(C91Lfs*5) is classified as pathogenic in the context of Bardet-Biedl syndrome, BBS10-related. Sources cited for classification include the following: PMID 16582908, 20120035, 21209035, 20805367 and 24746959. Classification of NM_024685.3(BBS10):c.271dupT(C91Lfs*5) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Blueprint Genetics	RCV001074512	SCV001240099	pathogenic	Retinal dystrophy	2017-12-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487323	SCV001250249	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000001391	SCV001368386	pathogenic	Bardet-Biedl syndrome 10	2018-11-30	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM4,PP3,PP5.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000001391	SCV001430053	pathogenic	Bardet-Biedl syndrome 10	2020-01-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000001391	SCV001529431	pathogenic	Bardet-Biedl syndrome 10	2024-03-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000001391	SCV001752588	pathogenic	Bardet-Biedl syndrome 10	2021-06-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000001391	SCV002024439	pathogenic	Bardet-Biedl syndrome 10	2022-06-10	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000001391	SCV002579696	pathogenic	Bardet-Biedl syndrome 10	2022-06-02	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000001391	SCV002820322	pathogenic	Bardet-Biedl syndrome 10		criteria provided, single submitter	clinical testing	The frameshift duplication p.C91Lfs*5 in BBS10 (NM_024685.4) variant is known to be a common cause of Bardet-Biedl syndrome and is well-documented as a common founder mutation in several ethnic groups (Stoetzel C et al; Putoux A et al; Suspitsin et al). The variant has been reported to ClinVar as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV000168127	SCV003918824	pathogenic	Bardet-Biedl syndrome	2023-01-02	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003407252	SCV004111095	pathogenic	BBS10-related disorder	2023-12-30	criteria provided, single submitter	clinical testing	The BBS10 c.271dupT variant is predicted to result in a frameshift and premature protein termination (p.Cys91Leufs*5). This frameshift variant is the most common disease-causing variant found in BBS10 (Stoetzel et al. 2006. PubMed ID: 16582908; Mary et al. 2019. PubMed ID: 30614526). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in BBS10 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000001391	SCV000021541	pathogenic	Bardet-Biedl syndrome 10	2010-12-01	no assertion criteria provided	literature only
OMIM	RCV000144680	SCV000190013	pathogenic	Bardet-biedl syndrome 6/10, digenic	2010-12-01	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000709625	SCV000238414	pathogenic	Bardet-Biedl syndrome 1	2014-07-17	no assertion criteria provided	research	This patient is a carrier of a heterozygous pathogenic variant in the BBS10 gene associated with for Bardet-Biedl syndrome 10. The BBS10 variant (c.271dup; p.Cys91Leufs*5) identified in this patient is a frameshift variant, reported to be one of the most common pathogenic variants for Bardet Biedl syndrome (Stoetzel et al. 2006, PMID: 16582908).
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504690	SCV000599084	pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	RCV000168127	SCV000839559	pathogenic	Bardet-Biedl syndrome	2018-09-15	no assertion criteria provided	provider interpretation
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000168127	SCV000926505	pathogenic	Bardet-Biedl syndrome	2018-04-01	flagged submission	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000487323	SCV000926796	pathogenic	not provided	2018-04-01	no assertion criteria provided	research
Natera, Inc.	RCV000001391	SCV001462857	pathogenic	Bardet-Biedl syndrome 10	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000487323	SCV001807902	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000487323	SCV001923357	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000487323	SCV001951758	pathogenic	not provided		no assertion criteria provided	clinical testing