Submissions for variant NM_152618.3(BBS12):c.1574G>A (p.Arg525His)

gnomAD frequency: 0.00001  dbSNP: rs776730549

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203973	SCV000260745	likely pathogenic	Bardet-Biedl syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 525 of the BBS12 protein (p.Arg525His). This variant is present in population databases (rs776730549, gnomAD 0.003%). This missense change has been observed in individual(s) with BBS12-related disease (PMID: 20472660, 30614526). 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: 220303). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000499807	SCV000593598	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000668722	SCV000793369	uncertain significance	Bardet-Biedl syndrome 12	2017-08-23	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000668722	SCV000803620	uncertain significance	Bardet-Biedl syndrome 12	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Bardet-Biedl syndrome 12, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium .
Baylor Genetics	RCV000668722	SCV004211677	likely pathogenic	Bardet-Biedl syndrome 12	2024-03-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000668722	SCV005664841	likely pathogenic	Bardet-Biedl syndrome 12	2024-06-06	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	RCV000203973	SCV000839576	pathogenic	Bardet-Biedl syndrome	2018-09-15	no assertion criteria provided	provider interpretation
PreventionGenetics, part of Exact Sciences	RCV004745281	SCV005346962	likely pathogenic	BBS12-related disorder	2024-03-11	no assertion criteria provided	clinical testing	The BBS12 c.1574G>A variant is predicted to result in the amino acid substitution p.Arg525His. This variant along with a second variant in BBS12 has been reported in two patients with Bardet-Biedl / McKusick-Kaufman syndrome phenotype (Table S1, Billingsley et al. 2010. PubMed ID: 20472660; Table 1, Mary et al. 2019. PubMed ID: 30614526). We have also seen this variant in the compound heterozygous state with a frameshift variant in BBS12 in a patient tested at PreventionGenetics with Bardet-Biedl syndrome. This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.