Submissions for variant NM_152618.3(BBS12):c.1055A>C (p.Gln352Pro)

gnomAD frequency: 0.00005  dbSNP: rs767068756

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000735935	SCV001516281	uncertain significance	Bardet-Biedl syndrome	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 352 of the BBS12 protein (p.Gln352Pro). This variant is present in population databases (rs767068756, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Bardet-Biedl syndrome (PMID: 30614526). ClinVar contains an entry for this variant (Variation ID: 560429). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375584	SCV001572481	uncertain significance	not specified	2021-04-12	criteria provided, single submitter	clinical testing	Variant summary: BBS12 c.1055A>C (p.Gln352Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251302 control chromosomes, predominantly at a frequency of 0.00039 within the South Asian subpopulation in the gnomAD database. This frequency is somewhat lower than the maximum expected for a pathogenic variant in BBS12 causing Bardet-Biedl Syndrome (0.00076), allowing no conclusion about variant significance. The variant, c.1055A>C, has been reported in the literature in at least two apparently homozygous individuals with clinical features of Bardet-Biedl syndrome (Haer-Wigman_2017, Mary_2019). These data indicate that the variant maybe associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=1) or VUS (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV000678525	SCV004211665	likely pathogenic	Bardet-Biedl syndrome 12	2023-12-08	criteria provided, single submitter	clinical testing
Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	RCV004794437	SCV005415451	likely pathogenic	Retinal dystrophy	2024-05-27	criteria provided, single submitter	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678525	SCV000804598	uncertain significance	Bardet-Biedl syndrome 12	2016-09-01	no assertion criteria provided	clinical testing
Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	RCV000735935	SCV000839572	pathogenic	Bardet-Biedl syndrome	2018-09-15	no assertion criteria provided	provider interpretation