ClinVar Miner

Submissions for variant NM_001079866.2(BCS1L):c.550C>T (p.Arg184Cys)

gnomAD frequency: 0.00011  dbSNP: rs121908578
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000384654 SCV000329628 likely pathogenic not provided 2022-11-02 criteria provided, single submitter clinical testing Functional analysis found that the introduction of R184C into yeast with deletion of the BSC1L gene failed to rescue the cell line (Fernandez-Vizarra et al., 2007); 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: 17403714, 19285991, 17314340, 20518024, 22310368, 28322498, Gandelman2020[Case Report], 32375044, 31589614, 23220121, 18620006, 36157077, 33920624, 30582773)
Illumina Laboratory Services, Illumina RCV000034811 SCV000914902 likely pathogenic Mitochondrial complex III deficiency nuclear type 1 2024-04-24 criteria provided, single submitter clinical testing
Invitae RCV000384654 SCV002223333 pathogenic not provided 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 184 of the BCS1L protein (p.Arg184Cys). This variant is present in population databases (rs121908578, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with BCS1L-related conditions (PMID: 17314340, 17403714, 30582773). ClinVar contains an entry for this variant (Variation ID: 6171). 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 BCS1L protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BCS1L function (PMID: 17314340, 17403714). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001142702 SCV002598780 likely pathogenic GRACILE syndrome 2022-09-12 criteria provided, single submitter clinical testing Variant summary: BCS1L c.550C>T (p.Arg184Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251364 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in BCS1L causing GRACILE Syndrome (0.00018 vs 0.00047), allowing no conclusion about variant significance. c.550C>T has been reported in the literature in individuals affected with BCS1L-related disorders. These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and showed that this variant caused attenuated growth of yeast train (Hinson_2007, Fernandez-Vizarra_2007). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic/likely pathogenic n=4, VUS n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV003472990 SCV004210782 pathogenic Pili torti-deafness syndrome 2023-10-02 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004532300 SCV004741567 likely pathogenic BCS1L-related disorder 2024-01-15 criteria provided, single submitter clinical testing The BCS1L c.550C>T variant is predicted to result in the amino acid substitution p.Arg184Cys. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals affected with Björnstad syndrome/mitochondrial complex III deficiency, and functional studies support its pathogenicity (Hinson et al. 2007. PubMed ID: 17314340; Baker et al. 2019. PubMed ID: 30582773; Fernandez-Vizarra et al. 2007. PubMed ID: 17403714). However it is also documented in more than 40 heterozygous and one homozygous individual of unknown phenotype in the gnomAD database. Based on the collective information, we interpret this change as likely pathogenic.
OMIM RCV000006546 SCV000026729 pathogenic Bjornstad syndrome with mild mitochondrial complex III deficiency 2007-05-15 no assertion criteria provided literature only
OMIM RCV000034811 SCV000058373 pathogenic Mitochondrial complex III deficiency nuclear type 1 2007-05-15 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000384654 SCV000802828 likely pathogenic not provided 2016-02-26 no assertion criteria provided clinical testing
Natera, Inc. RCV001142702 SCV001455775 likely pathogenic GRACILE syndrome 2020-09-16 no assertion criteria provided clinical testing

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