Submissions for variant NM_024649.5(BBS1):c.670G>A (p.Glu224Lys)

gnomAD frequency: 0.00002  dbSNP: rs193922709

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029404	SCV000052052	uncertain significance	not specified	2021-09-02	criteria provided, single submitter	clinical testing	Variant summary: BBS1 c.670G>A (p.Glu224Lys) results in a conservative amino acid change located in the N-terminal domain (IPR032728) of the Bardet-Biedl syndrome 1 protein (BBS1) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251258 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.670G>A has been reported in the literature in one individual (Redin_2012). This report does not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Blueprint Genetics	RCV001074387	SCV001239965	pathogenic	Retinal dystrophy	2019-08-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001228905	SCV001401332	pathogenic	Bardet-Biedl syndrome	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 224 of the BBS1 protein (p.Glu224Lys). This variant is present in population databases (rs193922709, gnomAD 0.0009%). This missense change has been observed in individual(s) with BBS1-related conditions (PMID: 22773737; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 35753). 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 BBS1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001725934	SCV001961289	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	BBS1: PM3:Strong, PM2
GeneDx	RCV001725934	SCV002756627	uncertain significance	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 34906171, 31951201, 22773737, 25780760)
Baylor Genetics	RCV001835636	SCV004217363	likely pathogenic	Bardet-Biedl syndrome 1	2024-02-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001835636	SCV002094737	uncertain significance	Bardet-Biedl syndrome 1	2020-09-23	no assertion criteria provided	clinical testing