Submissions for variant NM_152618.3(BBS12):c.1531_1539del (p.Gln511_Gln513del)

dbSNP: rs752762669

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000503271	SCV000593597	likely pathogenic	Bardet-Biedl syndrome 12	2016-03-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000503271	SCV000680152	pathogenic	Bardet-Biedl syndrome 12	2017-09-08	criteria provided, single submitter	clinical testing
Invitae	RCV000801690	SCV000941480	pathogenic	Bardet-Biedl syndrome	2023-11-27	criteria provided, single submitter	clinical testing	This variant, c.1531_1539del, results in the deletion of 3 amino acid(s) of the BBS12 protein (p.Gln511_Gln513del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs752762669, gnomAD 0.007%). This variant has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 17160889, 20120035; Invitae). 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: 434492). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects BBS12 function (PMID: 20498079). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001073940	SCV001239505	likely pathogenic	Retinal dystrophy	2018-07-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000503271	SCV003826992	likely pathogenic	Bardet-Biedl syndrome 12	2022-01-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003419857	SCV004107409	likely pathogenic	BBS12-related condition	2024-01-04	criteria provided, single submitter	clinical testing	The BBS12 c.1531_1539del9 variant is predicted to result in an in-frame deletion (p.Gln511_Gln513del). This variant was reported in individuals with Bardet-Biedl syndrome (Stoetzel et al 2007. PubMed ID: 17160889; Hjortshøj et al. 2010. PubMed ID: 20120035). Functional studies using zebrafish suggest that this variant is deleterious (Supp. Table 4, Zaghloul et al. 2010. PubMed ID: 20498079). This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV000503271	SCV004211666	likely pathogenic	Bardet-Biedl syndrome 12	2023-09-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000801690	SCV004241180	likely pathogenic	Bardet-Biedl syndrome	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: BBS12 c.1531_1539delCAGATGCAA (p.Gln511_Gln513del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant allele was found at a frequency of 4e-05 in 251428 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BBS12 causing Bardet-Biedl Syndrome (4e-05 vs 0.00076), allowing no conclusion about variant significance. c.1531_1539delCAGATGCAA has been reported in the literature in individuals affected with Bardet-Biedl Syndrome (Stoetzel_2006, Hjortshj_2010, Manara_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant affects protein function (Zaghloul_2010). The following publications have been ascertained in the context of this evaluation (PMID: 21463199, 31964843, 20120035, 30718709, 31196119, 20648243, 17160889, 20498079). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787787	SCV000926797	likely pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research