Submissions for variant NM_031885.5(BBS2):c.1207C>T (p.Arg403Cys)

gnomAD frequency: 0.00004  dbSNP: rs766873519

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000665273	SCV000398059	uncertain significance	Bardet-Biedl syndrome 2	2017-04-27	criteria provided, single submitter	clinical testing	The BBS2 c.1207C>T (p.Arg403Cys) missense variant has been reported in one study in which it is found in two consanguineous families of Arab origin with Bardet-Biedl syndrome (Abu-Safieh et al. 2012). In one family, the single affected proband carried the variant in a homozygous state, while in the second family the variant was carried in a heterozygous state in three affected siblings, who also carried variants in three other BBS genes of unknown zygosity. The p.Arg403Cys variant was absent from 96 ethnically matched controls but is reported at a frequency of 0.00010 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg403Cys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Bardet-Biedl syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl	RCV000665273	SCV000789365	uncertain significance	Bardet-Biedl syndrome 2	2017-01-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850699	SCV002167471	likely pathogenic	Bardet-Biedl syndrome	2024-03-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 403 of the BBS2 protein (p.Arg403Cys). This variant is present in population databases (rs766873519, gnomAD 0.02%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 22353939). ClinVar contains an entry for this variant (Variation ID: 319857). 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 not expected to disrupt BBS2 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488537	SCV004241353	uncertain significance	not specified	2023-12-19	criteria provided, single submitter	clinical testing	Variant summary: BBS2 c.1207C>T (p.Arg403Cys) results in a non-conservative amino acid change located in the Ciliary BBSome complex subunit 2, C-terminal domain (IPR029333) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251492 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BBS2 causing Bardet-Biedl Syndrome (6.8e-05 vs 0.00098). c.1207C>T has been reported in the literature in at least one homozygous individuals affected with Bardet-Biedl Syndrome (e.g., Abu-Safieh_2012, Shaheen_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22353939, 27894351). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Breakthrough Genomics, Breakthrough Genomics	RCV004694280	SCV005194399	uncertain significance	not provided		criteria provided, single submitter	not provided
GeneDx	RCV004694280	SCV005324989	uncertain significance	not provided	2024-02-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27894351, 22353939)
Fulgent Genetics, Fulgent Genetics	RCV005016707	SCV005644031	uncertain significance	Bardet-Biedl syndrome 2; Retinitis pigmentosa 74	2024-04-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544576	SCV004770336	uncertain significance	BBS2-related disorder	2024-05-17	no assertion criteria provided	clinical testing	The BBS2 c.1207C>T variant is predicted to result in the amino acid substitution p.Arg403Cys. This variant has been reported in the homozygous state in one individual with Bardet-Biedl syndrome and in the heterozygous state in another individual who also carried other rare variants in Bardet-Biedl syndrome-related genes (Abu-Safieh et al. 2012. PubMed ID: 22353939). The authors did not provide any functional studies to help assess the pathogenicity of the c.1207C>T (p.Arg403Cys) variant. This variant is reported in 0.010% 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.