ClinVar Miner

Submissions for variant NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter)

gnomAD frequency: 0.00012  dbSNP: rs121917777
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169202 SCV000220452 likely pathogenic Bardet-Biedl syndrome 2014-06-25 criteria provided, single submitter literature only
Invitae RCV000169202 SCV000759871 pathogenic Bardet-Biedl syndrome 2024-01-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu549*) in the BBS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS1 are known to be pathogenic (PMID: 12118255, 21520335, 27032803). This variant is present in population databases (rs121917777, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 12118255, 15770229, 16327777, 21517826, 21642631, 22410627, 24746959). ClinVar contains an entry for this variant (Variation ID: 12144). 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 RCV000169202 SCV000918634 pathogenic Bardet-Biedl syndrome 2017-11-28 criteria provided, single submitter clinical testing Variant summary: The BBS1 c.1645G>T (p.Glu549X) variant results in a premature termination codon, predicted to cause a truncated or absent BBS1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/246270 control chromosomes at a frequency of 0.0000162, which does not exceed the estimated maximal expected allele frequency of a pathogenic BBS1 variant (0.0009449). The variant has been reported in numerous affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
GeneDx RCV001008645 SCV001168419 pathogenic not provided 2021-11-29 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 27788217, 21642631, 12118255, 21517826, 12677556, 16327777, 22410627, 24746959, 15770229, 31589614, 34792930, 34526762, 32037395)
Baylor Genetics RCV000012927 SCV001521567 pathogenic Bardet-Biedl syndrome 1 2019-01-11 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 12118255, 21642631, 24746959, 27788217]
Fulgent Genetics, Fulgent Genetics RCV000012927 SCV001752830 pathogenic Bardet-Biedl syndrome 1 2022-04-09 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001723562 SCV001950210 pathogenic Retinitis pigmentosa 2021-04-01 criteria provided, single submitter curation The p.Glu549Ter variant in BBS1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PS1, PM2. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000012927 SCV002507051 pathogenic Bardet-Biedl syndrome 1 2022-05-04 criteria provided, single submitter curation The heterozygous p.Glu549Ter variant in BBS1 was identified by our study, along with another pathogenic variant, in 1 individual with Bardet-Biedl syndrome 1. The variant has been reported in at least 11 Puerto Rican and French individuals with Bardet-Biedl syndrome 1 (PMID: 12118255, 21517826, 24746959, 29641573, 15770229, 16327777), segregated with disease in 2 affected relatives from 2 families (PMID: 15770229, 16327777) and has been identified in 0.009% (3/34584) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121917777). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 12144) as pathogenic by OMIM, Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America, and as likely pathogenic by Counsyl. This nonsense variant leads to a premature termination codon at position 549. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the BBS1 gene is an established disease mechanism in autosomal recessive Bardet-Biedl syndrome 1. The presence of this variant in at least 2 affected homozygotes, in combination with a reported pathogenic variant, and in at least 11 individuals with Bardet-Biedl syndrome 1 increases the likelihood that the p.Glu549Ter variant is pathogenic (VariationID: 12143; PMID: 12118255). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Bardet-Biedl Syndrome 1. ACMG/AMP Criteria applied: PM3_very-strong, PP1_moderate, PM2, PVS1_moderate (Richards 2015).
Ambry Genetics RCV002513001 SCV003745036 pathogenic Inborn genetic diseases 2021-11-12 criteria provided, single submitter clinical testing The c.1645G>T (p.E549*) alteration, located in exon 16 (coding exon 16) of the BBS1 gene, consists of a G to T substitution at nucleotide position 1645. This changes the amino acid from a glutamic acid (E) to a stop codon at amino acid position 549. This alteration occurs at the 3' terminus of the BBS1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 45/593 amino acids (7.6%) of the protein. Premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in the homozygous state and compound heterozygous state with various second disease-causing alterations in multiple patients with Bardet-Biedl syndrome (Mykytyn, 2002; Chen, 2011; Lindstrand, 2014; Sanchez-Navarro, 2018; Guardiola, 2021). Based on the available evidence, this alteration is classified as pathogenic.
PreventionGenetics, part of Exact Sciences RCV003934827 SCV004752793 pathogenic BBS1-related disorder 2024-01-31 criteria provided, single submitter clinical testing The BBS1 c.1645G>T variant is predicted to result in premature protein termination (p.Glu549*). This variant has been reported many times along with a second known causative variant or in the homozygous state in individuals with Bardet-Biedl syndrome or suspected non-syndromic retinitis pigmentosa (see for examples Mykytyn et al. 2002. PubMed ID: 12118255; Wang et al. 2016. PubMed ID: 27788217). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in BBS1 are expected to be pathogenic, and this variant has been classified as pathogenic by the majority of submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/12144). Given the evidence, we interpret c.1645G>T (p.Glu549*) as pathogenic.
OMIM RCV000012927 SCV000033168 pathogenic Bardet-Biedl syndrome 1 2002-08-01 no assertion criteria provided literature only
Natera, Inc. RCV000012927 SCV001456343 pathogenic Bardet-Biedl syndrome 1 2020-09-16 no assertion criteria provided clinical testing

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