NM_001079866.2(BCS1L):c.166C>T (p.Arg56Ter) AND Mitochondrial complex III deficiency nuclear type 1

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Nov 3, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000006544.15

Allele description [Variation Report for NM_001079866.2(BCS1L):c.166C>T (p.Arg56Ter)]

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

Gene:

BCS1L:BCS1 homolog, ubiquinol-cytochrome c reductase complex chaperone [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q35

Genomic location:

Preferred name:

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

Other names:

p.R56*:CGA>TGA

HGVS:

NC_000002.12:g.218661153C>T
NG_008018.1:g.6498C>T
NG_033099.1:g.3388G>A
NM_001079866.2:c.166C>TMANE SELECT
NM_001257342.2:c.166C>T
NM_001257343.2:c.166C>T
NM_001257344.2:c.166C>T
NM_001318836.2:c.-40-253C>T
NM_001320717.2:c.166C>T
NM_001371443.1:c.166C>T
NM_001371444.1:c.166C>T
NM_001371446.1:c.166C>T
NM_001371447.1:c.166C>T
NM_001371448.1:c.166C>T
NM_001371449.1:c.166C>T
NM_001371450.1:c.166C>T
NM_001371451.1:c.-40-253C>T
NM_001371452.1:c.-41-606C>T
NM_001371453.1:c.-311C>T
NM_001371454.1:c.-311C>T
NM_001371455.1:c.-311C>T
NM_001371456.1:c.-311C>T
NM_001374085.1:c.166C>T
NM_001374086.1:c.-311C>T
NM_004328.5:c.166C>T
NP_001073335.1:p.Arg56Ter
NP_001244271.1:p.Arg56Ter
NP_001244272.1:p.Arg56Ter
NP_001244273.1:p.Arg56Ter
NP_001307646.1:p.Arg56Ter
NP_001358372.1:p.Arg56Ter
NP_001358373.1:p.Arg56Ter
NP_001358375.1:p.Arg56Ter
NP_001358376.1:p.Arg56Ter
NP_001358377.1:p.Arg56Ter
NP_001358378.1:p.Arg56Ter
NP_001358379.1:p.Arg56Ter
NP_001361014.1:p.Arg56Ter
NP_004319.1:p.Arg56Ter
NP_004319.1:p.Arg56Ter
LRG_539t1:c.166C>T
LRG_539:g.6498C>T
LRG_539p1:p.Arg56Ter
NC_000002.11:g.219525876C>T
NM_001079866.1:c.166C>T
NM_001257342.1:c.166C>T
NM_004328.4:c.166C>T
NR_163955.1:n.1178C>T

Protein change:

R56*; ARG56TER

Links:

OMIM: 603647.0007; dbSNP: rs121908576

NCBI 1000 Genomes Browser:

rs121908576

Molecular consequence:

NM_001371453.1:c.-311C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001371454.1:c.-311C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001371455.1:c.-311C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001371456.1:c.-311C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001374086.1:c.-311C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001318836.2:c.-40-253C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001371451.1:c.-40-253C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001371452.1:c.-41-606C>T - intron variant - [Sequence Ontology: SO:0001627]
NR_163955.1:n.1178C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001079866.2:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001257342.2:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001257343.2:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001257344.2:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001320717.2:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001371443.1:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001371444.1:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001371446.1:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001371447.1:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001371448.1:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001371449.1:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001371450.1:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001374085.1:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004328.5:c.166C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Mitochondrial complex III deficiency nuclear type 1
Identifiers:: MONDO: MONDO:0007415; MedGen: C3541471; Orphanet: 254902; OMIM: 124000

Recent activity

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PREDICTED: probable cysteine--tRNA ligase, mitochondrial [Odobenus rosmarus dive...
PREDICTED: probable cysteine--tRNA ligase, mitochondrial [Odobenus rosmarus divergens]
gi|472380499|ref|XP_004409652.1|

Protein
Homo sapiens dystrobrevin binding protein 1 (DTNBP1), RefSeqGene (LRG_588) on ch...
Homo sapiens dystrobrevin binding protein 1 (DTNBP1), RefSeqGene (LRG_588) on chromosome 6
gi|219842268|ref|NG_009309.1||gnl|L G_588

Nucleotide
teneurin-4 [Homo sapiens]
teneurin-4 [Homo sapiens]
gi|169790825|ref|NP_001092286.2|

Protein
PAS_chr4_0438 [Komagataella phaffii GS115]
PAS_chr4_0438 [Komagataella phaffii GS115]
Gene ID:8200994

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000026727	OMIM	no assertion criteria provided	Pathogenic (Aug 30, 2003)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000236540	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	criteria provided, single submitter (Courtagen Life Sciences Classifications)	Pathogenic (Mar 5, 2015)	paternal	clinical testing	Citation Link,
SCV001572922	Genomic Medicine Lab, University of California San Francisco - CSER-P3EGS	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 12, 2019)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002512445	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002557254	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12215968, 19508421, 25741868
SCV002588786	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12215968, 12910490, 19508421, 22277166, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L.

Visapää I, Fellman V, Vesa J, Dasvarma A, Hutton JL, Kumar V, Payne GS, Makarow M, Van Coster R, Taylor RW, Turnbull DM, Suomalainen A, Peltonen L.

Am J Hum Genet. 2002 Oct;71(4):863-76. Epub 2002 Sep 5.

PubMed [citation]

PMID:: 12215968
PMCID:: PMC378542

Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene.

De Meirleir L, Seneca S, Damis E, Sepulchre B, Hoorens A, Gerlo E, García Silva MT, Hernandez EM, Lissens W, Van Coster R.

Am J Med Genet A. 2003 Aug 30;121A(2):126-31.

PubMed [citation]

PMID:: 12910490

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000026727.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

For discussion of the arg56-to-ter (R56X) mutation in the BCS1L gene that was found in compound heterozygous state in Spanish sibs with fatal infantile complex III deficiency (MC3DN1; 124000) by De Meirleir et al. (2003), see 603647.0006.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Courtagen Diagnostics Laboratory, Courtagen Life Sciences, SCV000236540.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Medicine Lab, University of California San Francisco - CSER-P3EGS, SCV001572922.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512445.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557254.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From DASA, SCV002588786.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 16, 2024

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