Submissions for variant NM_031885.5(BBS2):c.98C>A (p.Ala33Asp)

gnomAD frequency: 0.00001  dbSNP: rs797045155

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380380	SCV001578425	pathogenic	Bardet-Biedl syndrome	2023-07-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 33 of the BBS2 protein (p.Ala33Asp). This variant is present in population databases (rs797045155, gnomAD 0.003%). This missense change has been observed in individual(s) with Bardet-Biedl syndrome and/or nonsyndromic retinitis pigmentosa (PMID: 25541840; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209042). 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 BBS2 protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000675055	SCV001976998	likely pathogenic	Bardet-Biedl syndrome 2	2021-10-01	criteria provided, single submitter	clinical testing	PM2, PP3, PP4, PP5
Myriad Genetics, Inc.	RCV000675055	SCV002060274	uncertain significance	Bardet-Biedl syndrome 2	2021-11-15	criteria provided, single submitter	clinical testing	NM_031885.3(BBS2):c.98C>A(A33D) is a missense variant classified as a variant of uncertain significance in the context of Bardet-Biedl syndrome, BBS2-related. A33D has not been observed in cases with relevant disease. Functional assessments of this variant are not available in the literature. A33D has been observed in population frequency databases (gnomAD: AMR 0.003%). In summary, there is insufficient evidence to classify NM_031885.3(BBS2):c.98C>A(A33D) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
OMIM	RCV000190987	SCV000245874	pathogenic	Retinitis pigmentosa 74	2015-03-01	no assertion criteria provided	literature only
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002878	SCV001160911	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004539761	SCV004764088	uncertain significance	BBS2-related disorder	2024-02-01	no assertion criteria provided	clinical testing	The BBS2 c.98C>A variant is predicted to result in the amino acid substitution p.Ala33Asp. This variant was reported in the compound heterozygous state in three siblings who presented with retinitis pigmentosa (Shevach et al. 2015. PubMed ID: 25541840). This variant was also described in the apparently homozygous state in at least two other individuals with retinitis pigmentosa or suspected Bardet-Biedl syndrome; however, additional clinical and familial details were not provided (Sharon et al. 2019. PubMed ID: 31456290, supplementary data; Marinakis et al. 2021. PubMed ID: 34008892). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.