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

gnomAD frequency: 0.00001  dbSNP: rs369691608

Total submissions: 5

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