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

gnomAD frequency: 0.00011  dbSNP: rs121908578

Total submissions: 12

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	uncertain significance	Mitochondrial complex III deficiency nuclear type 1	2018-10-30	criteria provided, single submitter	clinical testing	The BCS1L c.550C>T (p.Arg184Cys) variant has been reported in three studies and was found in three patients with complex III deficiency, including two compound heterozygotes and one heterozygote in whom a second variant was not detected (Hinson et al. 2007; Fernandez-Vizarra et al. 2007; Moran et al. 2010). The p.Arg184Cys variant was absent from a total of 510 control chromosomes (Hinson et al. 2007; Fernandez-Vizarra et al. 2007) and is reported at a frequency of 0.002858 in the Ashkenazi Jewish population of the Genome Aggregation Database. Of note, there is one homozygote in this population. Functional studies in yeast showed that strains carrying the p.Arg184Cys variant displayed a significant reduction of cytochrome content and respiratory activity in addition to decreased levels of fully assembled complex III (Fernandez-Vizarra et al. 2007). Fibroblasts from the patient heterozygous for the p.Arg184Cys variant displayed only a mild-to-moderate reduction in growth rate, enzyme activity, and complex assembly and similar levels of protein expression and normal reactive oxygen species compared to control fibroblasts (Moran et al. 2010). Based on the evidence, the p.Arg184Cys 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.
Illumina Laboratory Services, Illumina	RCV001142701	SCV001303174	uncertain significance	Leigh syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001142702	SCV001303175	uncertain significance	GRACILE syndrome	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
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	RCV003914815	SCV004741567	likely pathogenic	BCS1L-related condition	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