NM_001079866.2(BCS1L):c.134G>A (p.Arg45His) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Mar 7, 2024
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:: RCV001243753.17

Allele description [Variation Report for NM_001079866.2(BCS1L):c.134G>A (p.Arg45His)]

NM_001079866.2(BCS1L):c.134G>A (p.Arg45His)

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.134G>A (p.Arg45His)

HGVS:

NC_000002.12:g.218661121G>A
NG_008018.1:g.6466G>A
NG_033099.1:g.3420C>T
NM_001079866.2:c.134G>AMANE SELECT
NM_001257342.2:c.134G>A
NM_001257343.2:c.134G>A
NM_001257344.2:c.134G>A
NM_001318836.2:c.-40-285G>A
NM_001320717.2:c.134G>A
NM_001371443.1:c.134G>A
NM_001371444.1:c.134G>A
NM_001371446.1:c.134G>A
NM_001371447.1:c.134G>A
NM_001371448.1:c.134G>A
NM_001371449.1:c.134G>A
NM_001371450.1:c.134G>A
NM_001371451.1:c.-40-285G>A
NM_001371452.1:c.-41-638G>A
NM_001371453.1:c.-343G>A
NM_001371454.1:c.-343G>A
NM_001371455.1:c.-343G>A
NM_001371456.1:c.-343G>A
NM_001374085.1:c.134G>A
NM_001374086.1:c.-343G>A
NM_004328.5:c.134G>A
NP_001073335.1:p.Arg45His
NP_001244271.1:p.Arg45His
NP_001244272.1:p.Arg45His
NP_001244273.1:p.Arg45His
NP_001307646.1:p.Arg45His
NP_001358372.1:p.Arg45His
NP_001358373.1:p.Arg45His
NP_001358375.1:p.Arg45His
NP_001358376.1:p.Arg45His
NP_001358377.1:p.Arg45His
NP_001358378.1:p.Arg45His
NP_001358379.1:p.Arg45His
NP_001361014.1:p.Arg45His
NP_004319.1:p.Arg45His
NP_004319.1:p.Arg45His
LRG_539t1:c.134G>A
LRG_539:g.6466G>A
LRG_539p1:p.Arg45His
NC_000002.11:g.219525844G>A
NM_004328.4:c.134G>A
NR_163955.1:n.1146G>A

Protein change:

R45H

Links:

dbSNP: rs754414354

NCBI 1000 Genomes Browser:

rs754414354

Molecular consequence:

NM_001371453.1:c.-343G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001371454.1:c.-343G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001371455.1:c.-343G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001371456.1:c.-343G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001374086.1:c.-343G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001318836.2:c.-40-285G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001371451.1:c.-40-285G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001371452.1:c.-41-638G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001079866.2:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001257342.2:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001257343.2:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001257344.2:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001320717.2:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371443.1:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371444.1:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371446.1:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371447.1:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371448.1:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371449.1:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001371450.1:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001374085.1:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004328.5:c.134G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_163955.1:n.1146G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001416934	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 7, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 28322498, 12910490, 20727375, 28492532
SCV002504356	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Mar 10, 2022)	germline	clinical testing	Citation Link,
SCV003819585	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001416934

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 7, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002504356

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Mar 10, 2022)

germline

clinical testing

Citation Link,

SCV003819585

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 3, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel compound heterozygous mutations in BCS1L gene causing Bjornstad syndrome in two siblings.

Falco M, Franzè A, Iossa S, De Falco L, Gambale A, Marciano E, Iolascon A.

Am J Med Genet A. 2017 May;173(5):1348-1352. doi: 10.1002/ajmg.a.38146. Epub 2017 Mar 21.

PubMed [citation]

PMID:: 28322498

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001416934.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 45 of the BCS1L protein (p.Arg45His). This variant is present in population databases (rs754414354, gnomAD 0.004%). This missense change has been observed in individual(s) with Bjornstad syndrome (PMID: 28322498). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 554577). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BCS1L protein function with a positive predictive value of 95%. This variant disrupts the p.Arg45 amino acid residue in BCS1L. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12910490, 20727375). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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

From GeneDx, SCV002504356.2

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28322498)

#	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 Revvity Omics, Revvity, SCV003819585.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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