Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_031885.5(BBS2):c.1015C>T(p.Arg339*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
BBS2 (HGNC:967): (Bardet-Biedl syndrome 2) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse and the similar phenotypes exhibited by mutations in BBS gene family members is likely due to their shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene forms a multiprotein BBSome complex with seven other BBS proteins.[provided by RefSeq, Oct 2014]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-56502382-G-A is Pathogenic according to our data. Variant chr16-56502382-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56502382-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-56502382-G-A is described in Lovd as [Pathogenic].
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Dec 10, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Feb 26, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Bardet-Biedl syndrome Pathogenic:2
Jun 03, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change creates a premature translational stop signal (p.Arg339*) in the BBS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS2 are known to be pathogenic (PMID: 11285252, 20177705, 24608809, 26518167). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Bardet-Biedl syndrome (PMID: 27894351, 28387813). ClinVar contains an entry for this variant (Variation ID: 35754). For these reasons, this variant has been classified as Pathogenic. -
Aug 24, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BBS2 c.1015C>T (p.Arg339X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251404 control chromosomes (gnomAD). c.1015C>T has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (e.g. Shaheen_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Retinitis pigmentosa 74 Pathogenic:1
Oct 04, 2024
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research
PVS1,PM2,PM3 -
not provided Pathogenic:1
Jan 10, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32055034, 31630094, 31589614, 28387813, 33777945, 31725702, 27894351) -