Submissions for variant NM_001079866.2(BCS1L):c.547C>T (p.Arg183Cys)

gnomAD frequency: 0.00008  dbSNP: rs144885874

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000006550	SCV000245582	likely pathogenic	Mitochondrial complex III deficiency nuclear type 1	2014-12-15	criteria provided, single submitter	clinical testing	The p.Arg183Cys variant in BCS1L has been identified in 1 compound heterozygous individual with Mitochondrial complex III deficiency (Fernandez-Vizarra 2007). The p.Arg183Cys variant has been identified in 0.023% (1/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs144885874). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies suggest that this variant impacts protein function (Fernandez-Vizarra 2007). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg183Cys variant is likely pathogenic.
GeneDx	RCV000521027	SCV000617286	pathogenic	not provided	2018-10-30	criteria provided, single submitter	clinical testing	The R183C pathogenic variant in the BCS1L gene has been reported previously in combination with another BCS1L variant in an individual with early-onset encephalopathy and complex III deficiency (Fernandez-Vizarra et al., 2007). The R183C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R183C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional analysis found that the introduction of R183C into yeast with deletion of the BSC1L gene failed to rescue the cell line (Fernandez-Vizarra et al., 2007). We interpret R183C as a pathogenic variant.
Invitae	RCV000521027	SCV002265125	likely pathogenic	not provided	2024-01-04	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 183 of the BCS1L protein (p.Arg183Cys). This variant is present in population databases (rs144885874, gnomAD 0.008%). This missense change has been observed in individual(s) with Björnstad syndrome (PMID: 17403714). ClinVar contains an entry for this variant (Variation ID: 6174). 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: 17403714). This variant disrupts the p.Arg183 amino acid residue in BCS1L. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17314340). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Baylor Genetics	RCV003472991	SCV004210785	likely pathogenic	Pili torti-deafness syndrome	2024-03-28	criteria provided, single submitter	clinical testing
OMIM	RCV000006550	SCV000026733	pathogenic	Mitochondrial complex III deficiency nuclear type 1	2007-05-15	no assertion criteria provided	literature only
Counsyl	RCV000674245	SCV000799548	uncertain significance	GRACILE syndrome	2018-04-24	flagged submission	clinical testing