Submissions for variant NM_176824.3(BBS7):c.1603C>A (p.Pro535Thr)

gnomAD frequency: 0.00006  dbSNP: rs143700362

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001094937	SCV000447388	uncertain significance	Bardet-Biedl syndrome 7	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000263459	SCV001234722	uncertain significance	Bardet-Biedl syndrome	2022-06-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 535 of the BBS7 protein (p.Pro535Thr). This variant is present in population databases (rs143700362, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BBS7-related conditions. ClinVar contains an entry for this variant (Variation ID: 347481). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	RCV002265746	SCV002547733	uncertain significance	not specified	2022-05-11	criteria provided, single submitter	clinical testing	Variant summary: BBS7 c.1603C>A (p.Pro535Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251304 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BBS7 causing Bardet-Biedl Syndrome (7.6e-05 vs 0.00062), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1603C>A in individuals affected with Bardet-Biedl Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV001094937	SCV002776439	uncertain significance	Bardet-Biedl syndrome 7	2022-05-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003957800	SCV004774252	uncertain significance	BBS7-related condition	2024-03-01	criteria provided, single submitter	clinical testing	The BBS7 c.1603C>A variant is predicted to result in the amino acid substitution p.Pro535Thr. To our knowledge, this variant has not been reported in the literature in individuals with BBS7-related disease. This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.