ClinVar Miner

Submissions for variant NM_001079866.2(BCS1L):c.268C>T (p.Arg90Cys)

gnomAD frequency: 0.00001  dbSNP: rs369691608
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Raymond Lab,University of Cambridge RCV000850204 SCV000897742 likely pathogenic Intellectual disability 2019-02-13 criteria provided, single submitter research
Illumina Laboratory Services,Illumina RCV000778592 SCV000914899 uncertain significance Mitochondrial complex III deficiency nuclear type 1 2018-11-07 criteria provided, single submitter clinical testing The BCS1L c.268C>T (p.Arg90Cys) variant is a missense variant that has been reported in one study, in which it is found in a compound heterozygous state with another missense variant in one individual with mitochondrial respiratory chain complex III deficiency (Calvo et al. 2012). The other missense variant had been reported previously and is a recognized causative variant for this disorder. Control data are unavailable for this variant, which is reported at a frequency of 0.000012 in the Total population of the Genome Aggregation Database. The Arg90 residue is highly conserved and the substitution alters the charge of the highly conserved residue within a functionally important domain. Western blot analysis showed that although BCS1L protein levels are within normal limits, the individual carrying the variant shows a reduction of the complex III protein, UQCRFS1. Based on the limited evidence, the p.Arg90Cys variant is 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.
Invitae RCV001855960 SCV002309702 likely pathogenic not provided 2021-10-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 90 of the BCS1L protein (p.Arg90Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs369691608, ExAC 0.003%). This variant has been observed in individual(s) with clinical features of BCS1L-related conditions (PMID: 22277967, 31316545, 32581362). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 625207). 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. Experimental studies have shown that this variant affects BCS1L function (PMID: 22277967). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003574 SCV001161951 pathogenic Microcephaly; Sparse hair; Intellectual disability, severe; Movement disorder no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV001003575 SCV001161952 pathogenic Microcephaly; Sparse hair; Movement disorder no assertion criteria provided research

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