Submissions for variant NM_001079866.2(BCS1L):c.166C>T (p.Arg56Ter)

gnomAD frequency: 0.00030  dbSNP: rs121908576

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000006544	SCV000236540	pathogenic	Mitochondrial complex III deficiency nuclear type 1	2015-03-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000195481	SCV000251198	pathogenic	not provided	2024-05-22	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22277166, 34662929, 19389488, 30634555, 30582773, 31214239, 26990548, 28496993, 31589614, 28128857, 31345219, 38256023, 37236975, 12215968, 34650211, 31435670, 12910490, 20518024, 19508421)
Illumina Laboratory Services, Illumina	RCV000260660	SCV000427428	pathogenic	BCS1L-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	The BCS1L c.166C>T (p.Arg56Ter) variant is a stop-gained variant which is predicted to truncate the protein. The p.Arg56Ter variant has been reported in at least five studies in a total of six individuals with mitochondrial respiratory chain complex III deficiency or GRACILE syndrome, including an affected sibling pair, in a compound heterozygous state (Visapaa et al. 2002; De Meirleir et al. 2003; Gil-Borlado et al. 2009; Ramos-Arroyo et al. 2009; Lynn et al. 2012). The variant was also found in a heterozygous state in an unaffected parent of the affected sibling pair who exhibited isolated biochemical complex III deficiency in the liver (De Meirleir et al. 2003). The p.Arg56Ter variant was absent from 400 controls, and is reported at a frequency of 0.00069 in the Latino population of the Exome Aggregation Consortium. Based on the evidence from the literature and the potential impact of stop-gained variants, the p.Arg56Ter variant is classified as pathogenic for BCS1L-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000195481	SCV000510767	pathogenic	not provided	2017-02-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000576565	SCV000698303	pathogenic	GRACILE syndrome	2016-07-22	criteria provided, single submitter	clinical testing	Variant summary: The BCS1L c.166C>T (p.Arg56X) variant results in a premature termination codon, predicted to cause a truncated or absent BCS1L protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. The variant is predicted to truncate N-terminal, P-loop and ATPase domains. Truncations downstream of this position (e.g. p.R186* and p.R291*, etc.) have been have been reported in patients with BCS1L-linked phenotypes in literature. Functional study shows that this variant drastically reduces the expression of mRNA (Gil-Borlado_2009). This variant was found in 23/122068 control chromosomes at a frequency of 0.0001884, which does not exceed the estimated maximal expected allele frequency of a pathogenic BCS1L variant (0.0025). This variant is found in several families/patients with complex III deficiency in compound heterozygous with other missense or promoter mutations. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000195481	SCV000854970	pathogenic	not provided	2018-01-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763069	SCV000893575	pathogenic	Pili torti-deafness syndrome; GRACILE syndrome; Leigh syndrome; Mitochondrial complex III deficiency nuclear type 1	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195481	SCV000959976	pathogenic	not provided	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg56*) in the BCS1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCS1L are known to be pathogenic (PMID: 12215968, 17314340, 19162478, 19508421, 22277166, 25895478). This variant is present in population databases (rs121908576, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with BCS1L-related conditions (PMID: 12215968, 12910490, 19508421, 22277166). ClinVar contains an entry for this variant (Variation ID: 6169). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000576565	SCV001194150	pathogenic	GRACILE syndrome	2020-01-06	criteria provided, single submitter	clinical testing	NM_004328.4(BCS1L):c.166C>T(R56*) is classified as pathogenic in the context of BCS1L-related disorders. Sources cited for classification include the following: PMID 12910490, 12215968, 22277166 and 20518024. Classification of NM_004328.4(BCS1L):c.166C>T(R56*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Genomic Medicine Lab, University of California San Francisco	RCV000006544	SCV001572922	pathogenic	Mitochondrial complex III deficiency nuclear type 1	2019-12-12	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000195481	SCV002009877	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000006544	SCV002512445	pathogenic	Mitochondrial complex III deficiency nuclear type 1	2022-01-28	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PM2 moderate, PM3 strong, PM3 moderate, PP1 supporting
CeGaT Center for Human Genetics Tuebingen	RCV000195481	SCV002544209	pathogenic	not provided	2022-05-01	criteria provided, single submitter	clinical testing	BCS1L: PVS1, PS4:Moderate
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000006544	SCV002557254	pathogenic	Mitochondrial complex III deficiency nuclear type 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bjornstad syndrome (MIM#262000), GRACILE syndrome (MIM#603358) and mitochondrial complex III deficiency, nuclear type (MIM#1124000). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (46 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in a compound heterozygous state in multiple individuals with mitochondrial complex III deficiency or GRACILE syndrome (ClinVar, PMID: 19508421, PMID: 12215968). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
DASA	RCV000006544	SCV002588786	pathogenic	Mitochondrial complex III deficiency nuclear type 1	2022-11-03	criteria provided, single submitter	clinical testing	The c.166C>T;p.Arg56* variant creates a premature translational stop signal in the BCS1L gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 6169; PMID: 12215968, PMID:12910490, PMID:19508421, PMID:22277166) - PS4. The variant is present at low allele frequencies population databases (rs121908576 – gnomAD 0.001626%; ABraOM 0.000854 frequency - https://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
Baylor Genetics	RCV003472989	SCV004210776	pathogenic	Pili torti-deafness syndrome	2024-03-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016249	SCV005650489	pathogenic	Pili torti-deafness syndrome; GRACILE syndrome; Mitochondrial complex III deficiency nuclear type 1	2024-05-09	criteria provided, single submitter	clinical testing
OMIM	RCV000006544	SCV000026727	pathogenic	Mitochondrial complex III deficiency nuclear type 1	2003-08-30	no assertion criteria provided	literature only
Natera, Inc.	RCV000576565	SCV001455773	pathogenic	GRACILE syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000260660	SCV005367067	pathogenic	BCS1L-related disorder	2024-04-01	no assertion criteria provided	clinical testing	The BCS1L c.166C>T variant is predicted to result in premature protein termination (p.Arg56*). This variant was reported as pathogenic in multiple individuals with autosomal recessive GRACILE syndrome or mitochondrial complex 3 deficiency (Visapaa. 2002. PubMed ID: 12215968; Morán. 2010. PubMed ID: 20518024; Lynn. 2012. PubMed ID: 22277166). This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in BCS1L are expected to be pathogenic. This variant is interpreted as pathogenic.