rs121908576
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001371453.1(BCS1L):βc.-311C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,614,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: π 0.00028 ( 0 hom., cov: 33)
Exomes π: 0.00016 ( 0 hom. )
Consequence
BCS1L
NM_001371453.1 5_prime_UTR_premature_start_codon_gain
NM_001371453.1 5_prime_UTR_premature_start_codon_gain
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.50
Genes affected
BCS1L (HGNC:1020): (BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone) This gene encodes a homolog of the S. cerevisiae bcs1 protein which is involved in the assembly of complex III of the mitochondrial respiratory chain. The encoded protein does not contain a mitochondrial targeting sequence but experimental studies confirm that it is imported into mitochondria. Mutations in this gene are associated with mitochondrial complex III deficiency and the GRACILE syndrome. Several alternatively spliced transcripts encoding two different isoforms have been described. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.362
PP5
Variant 2-218661153-C-T is Pathogenic according to our data. Variant chr2-218661153-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218661153-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BCS1L | NM_001079866.2 | c.166C>T | p.Arg56* | stop_gained | Exon 2 of 8 | ENST00000359273.8 | NP_001073335.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000283 AC: 43AN: 152188Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000167 AC: 42AN: 251472Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135914
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GnomAD4 exome AF: 0.000163 AC: 239AN: 1461890Hom.: 0 Cov.: 33 AF XY: 0.000147 AC XY: 107AN XY: 727248
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GnomAD4 genome 0.000282 AC: 43AN: 152306Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23AN XY: 74468
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:20
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mitochondrial complex III deficiency nuclear type 1 Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | Mar 05, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Dec 12, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 28, 2022 | ACMG classification criteria: PVS1 very strong, PM2 moderate, PM3 strong, PM3 moderate, PP1 supporting - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 30, 2003 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Nov 03, 2022 | 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 β 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | 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 - |
not provided Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 30, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 22, 2024 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2022 | BCS1L: PVS1, PS4:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2025 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 07, 2017 | - - |
GRACILE syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 22, 2016 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 06, 2020 | 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. - |
BCS1L-related disorder Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 01, 2024 | 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; MorΓ‘n. 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. - |
Pili torti-deafness syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Pili torti-deafness syndrome;C1864002:GRACILE syndrome;C2931891:Leigh syndrome;C3541471:Mitochondrial complex III deficiency nuclear type 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pili torti-deafness syndrome;C1864002:GRACILE syndrome;C3541471:Mitochondrial complex III deficiency nuclear type 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 09, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
0.79, 0.80
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at