Submissions for variant NM_152618.3(BBS12):c.1502C>T (p.Thr501Met)

gnomAD frequency: 0.00020  dbSNP: rs138011813

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000735937	SCV000932058	pathogenic	Bardet-Biedl syndrome	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 501 of the BBS12 protein (p.Thr501Met). This variant is present in population databases (rs138011813, gnomAD 0.05%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 17160889, 20472660). 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: 585190). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BBS12 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BBS12 function (PMID: 20080638, 20498079). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075675	SCV001241303	likely pathogenic	Retinal dystrophy	2019-03-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001784348	SCV002022017	likely pathogenic	Bardet-Biedl syndrome 12	2021-10-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000735937	SCV002547701	pathogenic	Bardet-Biedl syndrome	2022-05-26	criteria provided, single submitter	clinical testing	Variant summary: BBS12 c.1502C>T (p.Thr501Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251444 control chromosomes. c.1502C>T has been reported in the literature in multiple individuals affected with Bardet-Biedl Syndrome. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that mutant protein with p.T501M was significantly different to control in an in vivo assay (Zaghloul_2010). 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001784348	SCV002796418	pathogenic	Bardet-Biedl syndrome 12	2024-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV003235371	SCV003933037	likely pathogenic	not provided	2024-01-21	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect (PMID: 20498079); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17160889, 20472660, 30614526, 20498079)
New York Genome Center	RCV001784348	SCV004046482	pathogenic	Bardet-Biedl syndrome 12	2023-01-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001784348	SCV004211657	pathogenic	Bardet-Biedl syndrome 12	2024-03-02	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	RCV000735937	SCV000839575	pathogenic	Bardet-Biedl syndrome	2018-09-15	no assertion criteria provided	provider interpretation
Natera, Inc.	RCV001784348	SCV002084739	pathogenic	Bardet-Biedl syndrome 12	2020-07-23	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745562	SCV005349395	likely pathogenic	BBS12-related disorder	2024-04-08	no assertion criteria provided	clinical testing	The BBS12 c.1502C>T variant is predicted to result in the amino acid substitution p.Thr501Met. This variant has been reported in the compound heterozygous state in individuals with Bardet-Biedl syndrome (Stoetzel et al. 2007. PubMed ID: 17160889; Billingsley et al. 2010. PubMed ID: 20472660; Mary et al. 2019. PubMed ID: 30614526). This variant is reported in 0.052% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic.