Initial gene list and info collated by Miranda Durkie Sheffield Diagnostic Genetics Service December 2018 on behalf of the GMS Gastrohepatology specialist test group. Gene Symbol submitted: BCS1L; Suggested intial gene rating: Green; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given
Created: 7 Jan 2019, 4:42 p.m.
Comment when marking as ready: A number of cases have been reported in association with biallelic variants in BCS1L. There is a Finnish population with founder effect associated with GRACILE syndrome, where cholestasis is a feature. Reports in other populations suggest complex III deficiency. The cause for the difference in presentation is not clear. In both phenotypes the outcome is poor in view of multi-system dysfunction with death reported in infancy. I think that further evidence is needed about the mutational spectrum and clinical presentation. At present I think that this severe multi-system presentation is more likely to be picked up through other presenting routes e.g. mitochondrial / undiagnosed metabolic rather than a more focused cholestasis panel. Amber at present pending further information.
Created: 27 Jul 2018, 10:23 a.m.
Following discussion with the NHS GMS gastrohepatology specialist group on 14.01.19, it was agreed that although the phenotype associated with this gene is generally broader than isolated cholestasis, it would be appropriate to include on this panel as this might be the first presenting feature.
Created: 4 Feb 2019, 11:15 a.m.
Comment on list classification: Although GRACILE syndrome (growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death) has been reported in multiple individuals in association with BCS1L, 17 of these were Finnish cases homozygous for the same variant. Functional studies showed some evidence of pathogenicity (possible reduction in protein stability, failure to rescue BCS1L-deficient yeast in complementation studies). Variants in BCS1L have been reported in 9 additional unrelated patients from 7 families, however only 4/9 of these presented with cholestasis; unlike the Finnish patients, these 9 patients had complex III deficiency. Because of these differences in the phenotype in the non-Finnish cases, there is not sufficient evidence for this gene as a cause of GRACILE syndrome.
Created: 27 Jul 2018, 5:49 a.m.
Comment on publications: PIMD:11528392 reports 6 patients from 4 unrelated families with complex III deficiency, encephalopathy and renal tubulopathy; 2/6 also had cholestasis. PMID:12215968 reports 17 Finnish patients with GRACILE syndrome, homozygous for the same variant in BCS1L, and an additional 3 unrelated British patients, all compound heterozygotes for 5 additional variants (one was heterozygous for the Finnish variant); all Finnish patients and 2/3 British patients had cholestasis.
Created: 27 Jul 2018, 5:36 a.m.
Gene added from King's College Hospital NHS Foundation Trust diagnostic cholestasis gene panel. This gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.
Created: 25 Jul 2018, 4:15 p.m.
Mode of inheritance
Source: Expert Review Amber was removed from gene: BCS1L
Source Other was added to BCS1L. Mode of inheritance for gene BCS1L was changed from to BIALLELIC, autosomal or pseudoautosomal Added phenotypes Cholestasis; GRACILE syndrome for gene: BCS1L Publications for gene BCS1L were changed from to 11528392; 12215968; 9792866
Source Expert Review Green was added to BCS1L. Rating Changed from Red List (low evidence) to Green List (high evidence)
gene: BCS1L was added gene: BCS1L was added to Cholestasis. Sources: NHS GMS Mode of inheritance for gene: BCS1L was set to