Submissions for variant NM_001079866.2(BCS1L):c.703G>A (p.Gly235Arg)

dbSNP: rs368486097

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255431	SCV000321416	likely pathogenic	not provided	2018-07-06	criteria provided, single submitter	clinical testing	The G235R variant in the BCS1L gene has been reported previously with another variant on the opposite allele (in trans) in two sisters with hearing loss and pili torti (Falco et al., 2017). The G235R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The G235R 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret G235R as a likely pathogenic variant.
Counsyl	RCV000670051	SCV000794862	uncertain significance	GRACILE syndrome	2017-10-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001329215	SCV001520590	uncertain significance	Mitochondrial complex III deficiency nuclear type 1	2020-07-28	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV000255431	SCV002229223	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 235 of the BCS1L protein (p.Gly235Arg). This variant is present in population databases (rs368486097, gnomAD 0.003%). This missense change has been observed in individual(s) with Björnstad syndrome (PMID: 28322498). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265046). 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%. For these reasons, this variant has been classified as Pathogenic.