NM_001079866.2(BCS1L):c.170A>G (p.Asp57Gly) AND Mitochondrial complex III deficiency nuclear type 1

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 2, 2022
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:: RCV002472026.1

Allele description [Variation Report for NM_001079866.2(BCS1L):c.170A>G (p.Asp57Gly)]

NM_001079866.2(BCS1L):c.170A>G (p.Asp57Gly)

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.170A>G (p.Asp57Gly)

HGVS:

NC_000002.12:g.218661157A>G
NG_008018.1:g.6502A>G
NG_033099.1:g.3384T>C
NG_033099.2:g.3466T>C
NM_001079866.2:c.170A>GMANE SELECT
NM_001257342.2:c.170A>G
NM_001257343.2:c.170A>G
NM_001257344.2:c.170A>G
NM_001318836.2:c.-40-249A>G
NM_001320717.2:c.170A>G
NM_001371443.1:c.170A>G
NM_001371444.1:c.170A>G
NM_001371446.1:c.170A>G
NM_001371447.1:c.170A>G
NM_001371448.1:c.170A>G
NM_001371449.1:c.170A>G
NM_001371450.1:c.170A>G
NM_001371451.1:c.-40-249A>G
NM_001371452.1:c.-41-602A>G
NM_001371453.1:c.-307A>G
NM_001371454.1:c.-307A>G
NM_001371455.1:c.-307A>G
NM_001371456.1:c.-307A>G
NM_001374085.1:c.170A>G
NM_001374086.1:c.-307A>G
NM_004328.5:c.170A>G
NP_001073335.1:p.Asp57Gly
NP_001244271.1:p.Asp57Gly
NP_001244272.1:p.Asp57Gly
NP_001244273.1:p.Asp57Gly
NP_001244273.1:p.Asp57Gly
NP_001307646.1:p.Asp57Gly
NP_001358372.1:p.Asp57Gly
NP_001358373.1:p.Asp57Gly
NP_001358375.1:p.Asp57Gly
NP_001358376.1:p.Asp57Gly
NP_001358377.1:p.Asp57Gly
NP_001358378.1:p.Asp57Gly
NP_001358379.1:p.Asp57Gly
NP_001361014.1:p.Asp57Gly
NP_004319.1:p.Asp57Gly
NP_004319.1:p.Asp57Gly
LRG_539t1:c.170A>G
LRG_539t2:c.170A>G
LRG_539:g.6502A>G
LRG_539p1:p.Asp57Gly
LRG_539p2:p.Asp57Gly
NC_000002.11:g.219525880A>G
NM_001079866.1:c.170A>G
NM_001257344.1:c.170A>G
NM_004328.4:c.170A>G
NR_163955.1:n.1182A>G

Protein change:

D57G

Molecular consequence:

NM_001371453.1:c.-307A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001371454.1:c.-307A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001371455.1:c.-307A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001371456.1:c.-307A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001374086.1:c.-307A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001318836.2:c.-40-249A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001371451.1:c.-40-249A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001371452.1:c.-41-602A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001079866.2:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001257342.2:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001257343.2:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001257344.2:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001320717.2:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001371443.1:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001371444.1:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001371446.1:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001371447.1:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001371448.1:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001371449.1:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001371450.1:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001374085.1:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004328.5:c.170A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_163955.1:n.1182A>G - 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
SCV002768357	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17314340, 31435670, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002768357

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 2, 2022)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

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

Molecular genetic investigations identify new clinical phenotypes associated with BCS1L-related mitochondrial disease.

Oláhová M, Ceccatelli Berti C, Collier JJ, Alston CL, Jameson E, Jones SA, Edwards N, He L, Chinnery PF, Horvath R, Goffrini P, Taylor RW, Sayer JA.

Hum Mol Genet. 2019 Nov 15;28(22):3766-3776. doi: 10.1093/hmg/ddz202.

PubMed [citation]

PMID:: 31435670
PMCID:: PMC6935384

See all PubMed Citations (3)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768357.1

#	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 Likely 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). Missense variants have been reported to cause all conditions, with clinical severity dependant on the quantity and location of production of reactive oxygen species (PMID: 17314340). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated import auxiliary sequence (PMID: 31435670). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (p.(Arg69Cys)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited. (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

Last Updated: Dec 24, 2022

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