rs121908576

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001371453.1(BCS1L):​c.-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: 𝑓 0.00028 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

BCS1L
NM_001371453.1 5_prime_UTR_premature_start_codon_gain

Scores

2
4
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:20

Conservation

PhyloP100: 2.50
Variant links:
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
BCS1LNM_001079866.2 linkc.166C>T p.Arg56* stop_gained Exon 2 of 8 ENST00000359273.8 NP_001073335.1 Q9Y276A0A024R445

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BCS1LENST00000359273.8 linkc.166C>T p.Arg56* stop_gained Exon 2 of 8 1 NM_001079866.2 ENSP00000352219.3 Q9Y276

Frequencies

GnomAD3 genomes
AF:
0.000283
AC:
43
AN:
152188
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00157
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000279
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000167
AC:
42
AN:
251472
Hom.:
0
AF XY:
0.000184
AC XY:
25
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000491
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000211
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000163
AC:
239
AN:
1461890
Hom.:
0
Cov.:
33
AF XY:
0.000147
AC XY:
107
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.000425
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000184
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000282
AC:
43
AN:
152306
Hom.:
0
Cov.:
33
AF XY:
0.000309
AC XY:
23
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00157
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000279
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000160
Hom.:
0
Bravo
AF:
0.000291
ExAC
AF:
0.000189
AC:
23
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000237

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
Mar 05, 2015
Courtagen Diagnostics Laboratory, Courtagen Life Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 12, 2019
Genomic Medicine Lab, University of California San Francisco
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 28, 2022
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PM2 moderate, PM3 strong, PM3 moderate, PP1 supporting -

Aug 30, 2003
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Nov 03, 2022
DASA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Feb 02, 2022
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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 -

not provided Pathogenic:6
Jan 30, 2018
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 22, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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) -

May 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BCS1L: PVS1, PS4:Moderate -

Jan 08, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Feb 07, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

GRACILE syndrome Pathogenic:3
Jul 22, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 06, 2020
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

BCS1L-related disorder Pathogenic:2
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: 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. -

Apr 01, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: 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; 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
Mar 28, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Pili torti-deafness syndrome;C1864002:GRACILE syndrome;C2931891:Leigh syndrome;C3541471:Mitochondrial complex III deficiency nuclear type 1 Pathogenic:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Pili torti-deafness syndrome;C1864002:GRACILE syndrome;C3541471:Mitochondrial complex III deficiency nuclear type 1 Pathogenic:1
May 09, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.77
D
Vest4
0.79, 0.80
GERP RS
2.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908576; hg19: chr2-219525876; API