ClinVar Miner

Submissions for variant NM_001257342.2(BCS1L):c.166C>T (p.Arg56Ter) (rs121908576)

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Total submissions: 10
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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 2016-03-11 criteria provided, single submitter clinical testing The R56X pathogenic variant in the BCS1L gene has been reported previously in association with GRACILE syndrome and complex III deficiency in several unrelated cases who were found to be compound heterozygous for a second variant (Visapaa et al., 2002; Moran et al., 2010; Lynn et al., 2012). Quantitative RT-PCR studies showed that R56X variant was expressed at low levels in affected patient fibroblasts (Moran et al., 2010). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Illumina Clinical Services Laboratory,Illumina RCV000260660 SCV000427428 pathogenic BCS1L-Related Disorders 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
Counsyl RCV000576565 SCV000678020 likely pathogenic GRACILE syndrome 2015-10-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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
Invitae RCV000195481 SCV000959976 pathogenic not provided 2018-12-21 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. This variant is present in population databases (rs121908576, ExAC 0.07%). This variant has been observed in several individuals affected with BCS1L-related conditions (PMID: 12215968, 12910490, 22277166, 19508421). ClinVar contains an entry for this variant (Variation ID: 6169). Loss-of-function variants in BCS1L are known to be pathogenic (PMID: 17314340, 25895478). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000006544 SCV000026727 pathogenic Mitochondrial complex III deficiency, nuclear type 1 2003-08-30 no assertion criteria provided literature only

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