Submissions for variant NM_031885.5(BBS2):c.311A>C (p.Asp104Ala)

gnomAD frequency: 0.00003  dbSNP: rs121908179

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587645	SCV000699657	pathogenic	Bardet-Biedl syndrome	2016-06-30	criteria provided, single submitter	clinical testing	Variant summary: The c.311A>C (p.D104A) in BBS2 gene is a missense change that alters a conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00005 exclusively in individuals of European descent (0.000075). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in BBS2 gene (0.0008). Fedick (2014) reports the carrier frequency of 0.473% (0.0071%) for Jewish population. The variant of interest has been reported in multiple BBS pts in compound heterozygous state and in 2 homozygous individuals presented with nonsyndromic autosomal recessive RP (Shevach, 2014). Taking together, the variant was classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762969	SCV000893410	pathogenic	Bardet-Biedl syndrome 2; Retinitis pigmentosa 74	2022-01-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000587645	SCV001224789	pathogenic	Bardet-Biedl syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 104 of the BBS2 protein (p.Asp104Ala). This variant is present in population databases (rs121908179, gnomAD 0.1%). This missense change has been observed in individuals with Bardet-Biedl syndrome (PMID: 11567139, 21344540, 21642631, 23829372). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4577). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BBS2 function (PMID: 20498079). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001582466	SCV001819406	pathogenic	not provided	2019-10-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect suggestive of a dominant negative mode of action (Zaghloul et al., 2010); This variant is associated with the following publications: (PMID: 31456290, 20498079, 23829372, 11567139, 19402160, 25541840)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001002876	SCV001950217	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Asp104Ala variant in BBS2 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000190985	SCV002507053	pathogenic	Retinitis pigmentosa 74	2022-05-04	criteria provided, single submitter	curation	The heterozygous p.Asp104Ala variant in BBS2 was identified by our study, along with another pathogenic variant, in 1 individual with retinitis pigmentosa 74. The variant has been reported in at least 4 Ashkenazi Jewish individuals with retinitis pigmentosa 74 (PMID: 23829372), and has been identified in 0.1% (10/10080) of Ashkenazi Jewish and 0.0009% (1/113746) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121908179). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 4577) as pathogenic by Integrated Genetics/Laboratory Corporation of America, Invitae, OMIM, and Sharon lab, Hadassah-Hebrew University Medical Center, and as likely pathogenic by Counsyl and Fulgent Genetics. Animal models in zebrafish have shown that this variant causes retinitis pigmentosa 74 (PMID: 20498079). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in 2 affected homozygotes, in combination with a reported pathogenic variant, and in 4 individuals with retinitis pigmentosa 74 increases the likelihood that the p.Asp104Ala variant is pathogenic (VariationID: 4578; PMID: 23829372). In summary, this variant meets criteria to be classified as pathogenic for retinitis pigmentosa 74 in an autosomal recessive manner based on its disease-causing effect in an animal model, and its homozygous occurrence and occurrence with other pathogenic variants in trans in affected individuals. ACMG/AMP Criteria applied: PS3, PM3_strong, PP3 (Richards 2015).
New York Genome Center	RCV000762969	SCV003925420	pathogenic	Bardet-Biedl syndrome 2; Retinitis pigmentosa 74	2022-02-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000665304	SCV004214013	pathogenic	Bardet-Biedl syndrome 2	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000004839	SCV000025015	pathogenic	Bardet-biedl syndrome 1/2, digenic	2015-03-01	no assertion criteria provided	literature only
OMIM	RCV000190985	SCV000245872	pathogenic	Retinitis pigmentosa 74	2015-03-01	no assertion criteria provided	literature only
Counsyl	RCV000665304	SCV000789398	likely pathogenic	Bardet-Biedl syndrome 2	2017-01-30	no assertion criteria provided	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002876	SCV001160909	pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004532290	SCV004766229	pathogenic	BBS2-related disorder	2024-08-20	no assertion criteria provided	clinical testing	The BBS2 c.311A>C variant is predicted to result in the amino acid substitution p.Asp104Ala. This sequence variant has been reported in multiple individuals with Bardet-Biedl syndrome 2, retinitis pigmentosa 74, and cone-rod dystrophy (Katsanis et al. 2001. PubMed ID: 11567139; Consugar et al 2015. PubMed ID: 25412400; Shevach et al 2015. PubMed ID: 25541840). This variant is reported in 0.099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-56548399-T-G). This variant is interpreted as pathogenic.