ClinVar Miner

Submissions for variant NM_001079866.2(BCS1L):c.217C>T (p.Arg73Cys)

gnomAD frequency: 0.00006  dbSNP: rs140812286
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670706 SCV000795597 uncertain significance GRACILE syndrome 2017-11-09 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000778591 SCV000914898 uncertain significance Mitochondrial complex III deficiency nuclear type 1 2017-05-22 criteria provided, single submitter clinical testing The BCS1L c.217C>T (p.Arg73Cys) variant has been reported in two studies in the same individual with mitochondrial respiratory chain complex III deficiency in a compound heterozygous state with another missense variant (Fernandez-Vizarra et al. 2007; Invernizzi et al. 2012). The p.Arg73Cys variant was absent from 210 control alleles, but is reported at a frequency of 0.00315 in the Ashkenazi Jewish population of the Genome Aggregation Database. The Arg73 residue is conserved across multiple species. Patient fibroblasts showed 30% residual enzyme activity and 50% maximum respiration rate compared to wild type (Invernizzi et al. 2012). Growth complementation studies in yeast showed that the p.Arg73Cys variant alone was insufficient to cause a growth defect, but in the presence of the other missense variant from the compound heterozygous patient, growth was significantly reduced compared to wild type. A similar result was obtained looking at the mitochondrial cytochrome profile and respiration activity (Fernandez-Vizarra et al. 2007; Invernizzi et al. 2012). The evidence for this variant is limited. The p.Arg73Cys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for mitochondrial respiratory chain complex III deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen RCV001171821 SCV001334690 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Invitae RCV001171821 SCV001689654 likely benign not provided 2024-01-29 criteria provided, single submitter clinical testing
GeneDx RCV001171821 SCV004170563 uncertain significance not provided 2023-10-30 criteria provided, single submitter clinical testing Identified with a second variant in a patient with BCS1L-related mitochondrial complex III deficiency in the published literature (PMID: 17403714); 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: 22310368, 23168492, 30582773, 17403714)

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