Submissions for variant NM_024649.5(BBS1):c.442G>A (p.Asp148Asn)

gnomAD frequency: 0.00001  dbSNP: rs200688985

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799690	SCV000939365	pathogenic	Bardet-Biedl syndrome	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 148 of the BBS1 protein (p.Asp148Asn). This variant is present in population databases (rs200688985, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 23559858). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 645579). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BBS1 protein function. Experimental studies have shown that this missense change affects BBS1 function (PMID: 20498079). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001272375	SCV001521568	likely pathogenic	Bardet-Biedl syndrome 1	2024-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000799690	SCV001623243	likely pathogenic	Bardet-Biedl syndrome	2023-08-10	criteria provided, single submitter	clinical testing	Variant summary: BBS1 c.442G>A (p.Asp148Asn) results in a conservative amino acid change located in the Bardet-Biedl syndrome type 1, N-terminal (IPR032728) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251456 control chromosomes, predominantly at a frequency of 0.0023 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in BBS1 causing Bardet-Biedl Syndrome phenotype (0.0015), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin or could represent a higher carrier frequency in this population. c.442G>A has been reported in the literature in multiple comprehensively genotyped and clinically characterized individuals affected with Bardet-Biedl Syndrome (example, Beales_2003, Ajmal_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a characterization of functionally null outcome in a Zebra fish experimental system involving injection of morphilino against the BBS1 gene, evaluating defects in gastrulation, quantification of body axis shortening defect and rescue of the morphant phenotype by human BBS1 mRNA (Zaghloul_2010). The following publications have been ascertained in the context of this evaluation (PMID: 23559858, 12677556, 12872256, 20498079). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as (pathogenic/likely pathogenic, n=4; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV001272375	SCV002022014	likely pathogenic	Bardet-Biedl syndrome 1	2021-11-11	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001272375	SCV002060072	uncertain significance	Bardet-Biedl syndrome 1	2021-10-20	criteria provided, single submitter	clinical testing	NM_024649.4(BBS1):c.442G>A(D148N) is a missense variant classified as a variant of uncertain significance in the context of Bardet-Biedl syndrome, BBS1-related. D148N has been observed in cases with relevant disease (PMID: 12677556, 23559858, 31534736). Functional assessments of this variant are not available in the literature. D148N has been observed in population frequency databases (gnomAD: SAS 0.23%). In summary, there is insufficient evidence to classify NM_024649.4(BBS1):c.442G>A(D148N) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV002275136	SCV002563070	likely pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	BBS1: PM2, PM3, PP1, PS3:Supporting
GeneDx	RCV002275136	SCV002758987	uncertain significance	not provided	2022-06-02	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect (Zaghloul et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12677556, 12872256, 28844620, 29265593, 24705292, 31534736, 23559858, 20498079)
Lifecell International Pvt. Ltd	RCV001272375	SCV003914824	pathogenic	Bardet-Biedl syndrome 1		criteria provided, single submitter	clinical testing	A Homozygote Missense variant c.442G>A in Exon 5 of the BBS1 gene that results in the amino acid substitution p.Asp148Asn was identified. The observed variant has allele frequency of 0.00029/0.00 % in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic(ClinVar ID: 645579). Experimental studies have shown that this missense change affects BBS1 function(Zaghloul NA et al., 2010). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (Ajmal M et al., 2013). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001272375	SCV005052035	likely pathogenic	Bardet-Biedl syndrome 1	2024-02-01	criteria provided, single submitter	curation
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001272375	SCV005400447	pathogenic	Bardet-Biedl syndrome 1	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bardet-Biedl syndrome 1 (MIM#209900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The phenotypes associated with Bardet-Biedl syndrome are known to have both interfamilial and intrafamilial variation (PMID: 20301537). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (241 heterozygotes, 2 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4; 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ciliary BBSome complex subunit 1 (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar, as well as VUS entries. This variant has also been observed in multiple unrelated homozygous individuals with Bardet-Biedl syndrome (PMID: 23559858, 12677556). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV001272375	SCV005683590	uncertain significance	Bardet-Biedl syndrome 1	2024-05-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001272375	SCV001454311	likely pathogenic	Bardet-Biedl syndrome 1	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003938167	SCV004761930	uncertain significance	BBS1-related disorder	2024-07-25	no assertion criteria provided	clinical testing	The BBS1 c.442G>A variant is predicted to result in the amino acid substitution p.Asp148Asn. This variant was observed in individuals with Bardet-Biedl syndrome (Beales et al. 2003. PubMed ID: 12677556; Zaghloul et al. 2010. PubMed ID: 20498079; Hoskins et al. 2003. PubMed ID: 12872256). The authors did not publish the individuals' zygosity, if there was a second variant on the other allele, or family studies to help assess the pathogenicity of this variant. This variant was shown to segregate with Bardet-Biedl syndrome in one family (Shrestha et al 2019. PubMed ID: 31534736). A functional study in zebrafish indicated that this variant affects BBS1 function (Supplemental Table 4, Zaghloul et al 2010. PubMed ID: 20498079). This variant is reported in 0.23% of alleles in individuals of South Asian descent in gnomAD. This variant has interpretations ranging from uncertain significance to pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/645579/). Although we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain.