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

gnomAD frequency: 0.00001  dbSNP: rs200688985

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000799690	SCV000939365	pathogenic	Bardet-Biedl syndrome	2024-01-21	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). 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 BBS1 protein function with a negative predictive value of 80%. 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		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.
PreventionGenetics, part of Exact Sciences	RCV003938167	SCV004761930	uncertain significance	BBS1-related condition	2023-12-24	criteria provided, single submitter	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 is reported in 0.23% of alleles in individuals of South Asian descent in gnomAD, which is higher than expected for an unconfirmed primary cause of BBS. Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain.
Natera, Inc.	RCV001272375	SCV001454311	likely pathogenic	Bardet-Biedl syndrome 1	2020-09-16	no assertion criteria provided	clinical testing