rs121908578

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1PM5PP3PP5_Very_StrongBP4

The NM_001079866.2(BCS1L):c.550C>T(p.Arg184Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000836 in 1,614,064 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R184H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000081 ( 1 hom. )

Consequence

BCS1L
NM_001079866.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 4.89

Publications

16 publications found

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]

BCS1L Gene-Disease associations (from GenCC):

Bjornstad syndrome
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, Ambry Genetics, ClinGen, G2P
GRACILE syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
Leigh syndrome
Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, ClinGen
mitochondrial complex III deficiency nuclear type 1
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
mitochondrial complex III deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
renal tubulopathy-encephalopathy-liver failure syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BCS1L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001079866.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-218661849-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1480327.

PP3

Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 2-218661848-C-T is Pathogenic according to our data. Variant chr2-218661848-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.39996687). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCS1L	NM_001079866.2 link	c.550C>T	p.Arg184Cys	missense_variant	Exon 4 of 8	ENST00000359273.8	NP_001073335.1	Q9Y276A0A024R445

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCS1L	ENST00000359273.8 link	c.550C>T	p.Arg184Cys	missense_variant	Exon 4 of 8	1	NM_001079866.2	ENSP00000352219.3		Q9Y276

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000175

AC:

AN:

251364

AF XY:

0.000228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000807

AC:

118

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000908

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00222

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1112002

Other (OTH)

AF:

0.000232

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000112

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000790

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Feb 26, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 02, 2022

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Functional analysis found that the introduction of R184C into yeast with deletion of the BSC1L gene failed to rescue the cell line (Fernandez-Vizarra et al., 2007); 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: 17403714, 19285991, 17314340, 20518024, 22310368, 28322498, Gandelman2020[Case Report], 32375044, 31589614, 23220121, 18620006, 36157077, 33920624, 30582773) -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 184 of the BCS1L protein (p.Arg184Cys). This variant is present in population databases (rs121908578, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with BCS1L-related conditions (PMID: 17314340, 17403714, 30582773). ClinVar contains an entry for this variant (Variation ID: 6171). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BCS1L protein function. Experimental studies have shown that this missense change affects BCS1L function (PMID: 17314340, 17403714). For these reasons, this variant has been classified as Pathogenic. -

GRACILE syndrome

Pathogenic:2

Sep 12, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BCS1L c.550C>T (p.Arg184Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251364 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in BCS1L causing GRACILE Syndrome (0.00018 vs 0.00047), allowing no conclusion about variant significance. c.550C>T has been reported in the literature in individuals affected with BCS1L-related disorders. These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and showed that this variant caused attenuated growth of yeast train (Hinson_2007, Fernandez-Vizarra_2007). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic/likely pathogenic n=4, VUS n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Pili torti-deafness syndrome

Pathogenic:1

Mar 27, 2024

Baylor 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

Apr 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial complex III deficiency nuclear type 1

Pathogenic:1

May 15, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

BCS1L-related disorder

Pathogenic:1

Jan 15, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BCS1L c.550C>T variant is predicted to result in the amino acid substitution p.Arg184Cys. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals affected with Björnstad syndrome/mitochondrial complex III deficiency, and functional studies support its pathogenicity (Hinson et al. 2007. PubMed ID: 17314340; Baker et al. 2019. PubMed ID: 30582773; Fernandez-Vizarra et al. 2007. PubMed ID: 17403714). However it is also documented in more than 40 heterozygous and one homozygous individual of unknown phenotype in the gnomAD database. Based on the collective information, we interpret this change as likely pathogenic. -

Bjornstad syndrome with mild mitochondrial complex III deficiency

Pathogenic:1

May 15, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

D;D;.;D;D;D;D;D;D;D

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

.;D;D;.;.;.;.;.;.;D

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.40

T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

.;.;.;M;M;M;M;M;M;M

PhyloP100

4.9

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-4.3

D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0090

D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;.;D;D;D;D;D;D;D

Vest4

0.76, 0.76, 0.77, 0.76

MVP

0.98

MPC

1.8

ClinPred

0.51

GERP RS

5.9

PromoterAI

0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.85

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over