ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs193922709
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Total submissions: 7
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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
Invitae 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 uncertain significance not provided 2021-09-01 criteria provided, single submitter clinical testing
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 2023-09-25 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

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