ClinVar Miner

Submissions for variant NM_031885.4(BBS2):c.823C>T (p.Arg275Ter) (rs121908177)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000493074 SCV000338211 pathogenic not provided 2016-01-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000004834 SCV000398065 pathogenic Bardet-Biedl syndrome 2 2017-04-28 criteria provided, single submitter clinical testing The BBS2 c.823C>T (p.Arg275Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg275Ter variant has been reported in at least five studies in which it is found in at least nine patients with Bardet-Biedl syndrome including in six from four independent families in a homozygous state, in one in a compound heterozygous state, in one in a heterozygous state with a second missense variant where phase is unknown, and in one in a heterozygous state with two additional variants in the BBS1 gene (Katsanis et al. 2001; Nishimura et al. 2001; Badano et al. 2003; Chen et al. 2011; Janssen et al. 2011). The variant is also found in a heterozygous state in at least four unaffected family members (Katsanis et al. 2001; Badano et al. 2003). The p.Arg275Ter variant was absent from at least 312 control chromosomes but is reported at a frequency of 0.00076 in the European (Finnish) population of the Exome Aggregation Consortium. Based on the evidence and potential impact of stop-gained variants, the p.Arg275Ter 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 RCV000493074 SCV000582400 pathogenic not provided 2018-05-30 criteria provided, single submitter clinical testing The R275X variant in the BBS2 gene has been reported previously in the homozygous state in one family with Bardet-Biedl syndrome and as a heterozygous variant in another BBS family with possible BBS1 variants following analysis of polymorphic microsatellites from all BBS loci (Katsanis et al., 2001). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R275X variant is observed in 5/6614 (0.076%) alleles from individuals of European (Finnish) background in the ExAC dataset (Lek et al., 2016).
Invitae RCV000269226 SCV000636529 pathogenic Bardet-Biedl syndrome 2019-10-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg275*) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121908177, ExAC 0.08%). This variant has been reported in several individuals affected with Bardet-Biedl syndrome (PMID: 11567139, 11285252, 21642631, 12837689, 21052717). ClinVar contains an entry for this variant (Variation ID: 4572). Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762967 SCV000893408 pathogenic Bardet-Biedl syndrome 2; Retinitis pigmentosa 74 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000004834 SCV000918639 pathogenic Bardet-Biedl syndrome 2 2018-06-25 criteria provided, single submitter clinical testing Variant summary: BBS2 c.823C>T (p.Arg275X) 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. One truncation downstream of this position has been classified as pathogenic by our laboratory (eg. c.1864C>T, p.Arg622X). The variant allele was found at a frequency of 0.0002 in 277510 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in BBS2 causing Bardet-Biedl Syndrome (0.0002 vs 0.00085), allowing no conclusion about variant significance. The variant, c.823C>T, has been reported in the literature in multiple individuals affected with Bardet-Biedl Syndrome (Katsanis_2001, Nishimura_2001, Badano_2003). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Women's Health, Inc. RCV000004834 SCV001194096 pathogenic Bardet-Biedl syndrome 2 2019-12-20 criteria provided, single submitter clinical testing NM_031885.3(BBS2):c.823C>T(R275*) is classified as pathogenic in the context of BBS2-related Bardet-Biedl Syndrome. Sources cited for classification include the following: PMID 11567139 and 11285252. Classification of NM_031885.3(BBS2):c.823C>T(R275*) 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 RCV001074104 SCV001239673 pathogenic Retinal dystrophy 2019-01-05 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000493074 SCV001249675 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing
OMIM RCV000004834 SCV000025010 pathogenic Bardet-Biedl syndrome 2 2001-09-21 no assertion criteria provided literature only

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