NM_001079866.2(BCS1L):c.550C>T (p.Arg184Cys) AND Mitochondrial complex III deficiency nuclear type 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 30, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000034811.9

Allele description [Variation Report for NM_001079866.2(BCS1L):c.550C>T (p.Arg184Cys)]

NM_001079866.2(BCS1L):c.550C>T (p.Arg184Cys)

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.550C>T (p.Arg184Cys)

HGVS:

NC_000002.12:g.218661848C>T
NG_008018.1:g.7193C>T
NG_033099.1:g.2693G>A
NM_001079866.2:c.550C>TMANE SELECT
NM_001257342.2:c.550C>T
NM_001257343.2:c.550C>T
NM_001257344.2:c.550C>T
NM_001318836.2:c.190C>T
NM_001320717.2:c.550C>T
NM_001371443.1:c.550C>T
NM_001371444.1:c.550C>T
NM_001371446.1:c.550C>T
NM_001371447.1:c.550C>T
NM_001371448.1:c.550C>T
NM_001371449.1:c.550C>T
NM_001371450.1:c.550C>T
NM_001371451.1:c.190C>T
NM_001371452.1:c.49C>T
NM_001371453.1:c.49C>T
NM_001371454.1:c.49C>T
NM_001371455.1:c.49C>T
NM_001371456.1:c.49C>T
NM_001374085.1:c.550C>T
NM_001374086.1:c.49C>T
NM_004328.5:c.550C>T
NP_001073335.1:p.Arg184Cys
NP_001244271.1:p.Arg184Cys
NP_001244272.1:p.Arg184Cys
NP_001244273.1:p.Arg184Cys
NP_001305765.1:p.Arg64Cys
NP_001307646.1:p.Arg184Cys
NP_001358372.1:p.Arg184Cys
NP_001358373.1:p.Arg184Cys
NP_001358375.1:p.Arg184Cys
NP_001358376.1:p.Arg184Cys
NP_001358377.1:p.Arg184Cys
NP_001358378.1:p.Arg184Cys
NP_001358379.1:p.Arg184Cys
NP_001358380.1:p.Arg64Cys
NP_001358381.1:p.Arg17Cys
NP_001358382.1:p.Arg17Cys
NP_001358383.1:p.Arg17Cys
NP_001358384.1:p.Arg17Cys
NP_001358385.1:p.Arg17Cys
NP_001361014.1:p.Arg184Cys
NP_001361015.1:p.Arg17Cys
NP_004319.1:p.Arg184Cys
NP_004319.1:p.Arg184Cys
LRG_539t1:c.550C>T
LRG_539:g.7193C>T
LRG_539p1:p.Arg184Cys
NC_000002.11:g.219526571C>T
NM_001257342.2:c.550C>T
NM_004328.4:c.550C>T
NR_163955.1:n.1562C>T
Q9Y276:p.Arg184Cys

Protein change:

R17C; ARG184CYS

Links:

UniProtKB: Q9Y276#VAR_032090; OMIM: 603647.0009; dbSNP: rs121908578

NCBI 1000 Genomes Browser:

rs121908578

Molecular consequence:

NM_001079866.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001257342.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001257343.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001257344.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318836.2:c.190C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320717.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371443.1:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371444.1:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371446.1:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371447.1:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371448.1:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371449.1:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371450.1:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371451.1:c.190C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371452.1:c.49C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371453.1:c.49C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371454.1:c.49C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371455.1:c.49C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001371456.1:c.49C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374085.1:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374086.1:c.49C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004328.5:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_163955.1:n.1562C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Mitochondrial complex III deficiency nuclear type 1
Synonyms:: Complex 3 mitochondrial respiratory chain deficiency
Identifiers:: MONDO: MONDO:0007415; MedGen: C3541471; Orphanet: 254902; OMIM: 124000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000058373	OMIM	no assertion criteria provided	Pathogenic (May 15, 2007)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17314340, 17403714
SCV000914902	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Oct 30, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17403714, 17314340, 20518024 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000058373

OMIM

no assertion criteria provided

Pathogenic
(May 15, 2007)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000914902

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Oct 30, 2018)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Impaired complex III assembly associated with BCS1L gene mutations in isolated mitochondrial encephalopathy.

Fernandez-Vizarra E, Bugiani M, Goffrini P, Carrara F, Farina L, Procopio E, Donati A, Uziel G, Ferrero I, Zeviani M.

Hum Mol Genet. 2007 May 15;16(10):1241-52. Epub 2007 Apr 2.

PubMed [citation]

PMID:: 17403714

Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome.

Hinson JT, Fantin VR, Schönberger J, Breivik N, Siem G, McDonough B, Sharma P, Keogh I, Godinho R, Santos F, Esparza A, Nicolau Y, Selvaag E, Cohen BH, Hoppel CL, Tranebjaerg L, Eavey RD, Seidman JG, Seidman CE.

N Engl J Med. 2007 Feb 22;356(8):809-19.

PubMed [citation]

PMID:: 17314340

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000058373.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a sporadic case of Bjornstad syndrome (BJS; 262000) with mild mitochondrial complex III deficiency (MC3DN1; 124000), Hinson et al. (2007) found compound heterozygosity for 2 missense mutations in the BCS1L gene: arg184 to cys (R184C) and gly35 to arg (G35R; 603647.0010).

In a Moroccan girl with mitochondrial complex III deficiency (124000), Fernandez-Vizarra et al. (2007) identified compound heterozygosity for the R184C mutation and a 547C-T transition in exon 3 of the BCS1L gene, resulting in an arg183-to-cys (R183C; 603647.0012) substitution. She presented at age 9 months with acute psychomotor regression, hypotonia, and failure to thrive, which progressed to spastic quadriparesis and mental retardation associated with abnormal signal intensities in the thalami, basal ganglia, and periventricular white matter, consistent with an encephalopathy. Heart, liver, and kidneys were apparently unaffected, but she was also noted to have brittle hair. Studies in yeast showed that both mutations significantly reduced mitochondrial cytochrome content and respiratory activity, as well as caused a decreased incorporation of the Rieske iron-sulfur protein (UQCRFS1; 191327) into complex III. Further studies showed decreased levels of fully assembled complex III. The findings suggested that BCS1L is necessary for proper complex III assembly.

#	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 Illumina Laboratory Services, Illumina, SCV000914902.1

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

Description

The BCS1L c.550C>T (p.Arg184Cys) variant has been reported in three studies and was found in three patients with complex III deficiency, including two compound heterozygotes and one heterozygote in whom a second variant was not detected (Hinson et al. 2007; Fernandez-Vizarra et al. 2007; Moran et al. 2010). The p.Arg184Cys variant was absent from a total of 510 control chromosomes (Hinson et al. 2007; Fernandez-Vizarra et al. 2007) and is reported at a frequency of 0.002858 in the Ashkenazi Jewish population of the Genome Aggregation Database. Of note, there is one homozygote in this population. Functional studies in yeast showed that strains carrying the p.Arg184Cys variant displayed a significant reduction of cytochrome content and respiratory activity in addition to decreased levels of fully assembled complex III (Fernandez-Vizarra et al. 2007). Fibroblasts from the patient heterozygous for the p.Arg184Cys variant displayed only a mild-to-moderate reduction in growth rate, enzyme activity, and complex assembly and similar levels of protein expression and normal reactive oxygen species compared to control fibroblasts (Moran et al. 2010). Based on the evidence, the p.Arg184Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for mitochondrial respiratory chain complex III deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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

Last Updated: Mar 16, 2024

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