chr2-218661192-C-T

Position:

chr2-218661192-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001371453.1(BCS1L):c.-272C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000138 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

BCS1L
NM_001371453.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10U:2

Conservation

PhyloP100: 5.97

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 links:

BCS1L (HGNC:):

BCS1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-218661192-C-T is Pathogenic according to our data. Variant chr2-218661192-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 214160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218661192-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCS1L	NM_001079866.2 linkuse as main transcript	c.205C>T	p.Arg69Cys	missense_variant	2/8	ENST00000359273.8	NP_001073335.1	Q9Y276A0A024R445

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCS1L	ENST00000359273.8 linkuse as main transcript	c.205C>T	p.Arg69Cys	missense_variant	2/8	1	NM_001079866.2	ENSP00000352219.3		Q9Y276

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000755

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251480

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

207

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

102

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000468

Gnomad4 NFE exome

AF:

0.000155

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000105

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000755

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GRACILE syndrome

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 27, 2023	Variant summary: BCS1L c.205C>T (p.Arg69Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR014851) of 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 6.8e-05 in 251480 control chromosomes (gnomAD). This frequency is not higher than the estimated maximal expected for a pathogenic variant in BCS1L causing GRACILE Syndrome (0.00047), allowing no conclusion about variant significance. c.205C>T has been reported in the literature in multiple compound heterozygous individuals affected with symptoms that belong to the spectrum of BCS1L-related disorders (Olahova_2019, Hikmat_2021, Jou_2019, Posey_2017), all carrying a (likely) pathogenic variant in trans. These data indicate that the variant is likely to be associated with disease. At least one of these publications also reported experimental evidence, and demonstrated a partial loss of function in patient derived cells and in yeast complementation assays (Olahova_2019). Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=3) / likely pathogenic (n=3) or VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Mitochondrial complex III deficiency nuclear type 1

Pathogenic:2Uncertain:1

Uncertain significance, flagged submission	clinical testing	Baylor Genetics	May 01, 2016	Our laboratory reported dual molecular diagnoses in BCS1L (NM_004328.4:c.598C>T; NM_004328.4:c.205C>T ; in trans) and NLGN4X (NM_181332.1:c.301C>T) in an individual with short stature, failure to thrive, rickets, Fanconi syndrome, delayed motor milestones, absent speech, developmental regression, intellectual disability, hypotonia, seizure disorder, gait ataxia, abnormal movements (laughing behavior and tongue protrusion), dysmorphic features, microcephaly, history of seizure disorder. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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). 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 arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (18 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (12 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated import auxiliary sequence (PMID: 31435670). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS, but more commonly and recently as likely pathogenic. It has been reported in several compound heterozygous individuals with Leigh syndrome or aminoaciduria, seizures, bilateral sensorineural deafness and learning difficulties (ClinVar, LOVD, PMID: 31435670, PMID: 30634555). An additional individual with mitochondrial complex III deficiency has also been reported, but this individual had an additional hemizygous variant in the NLGN4X gene, which is considered part of a dual molecular diagnosis (PMID: 27959697, ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional analysis of this variant using the muscle biopsy of an affected individual and yeast complementation assays, has demonstrated that this variant has a partial loss of function effect on protein activity.Additionally, it reduced protein expression, mitochondrial respiratory activity and complex III activity (PMID: 31435670). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 69 of the BCS1L protein (p.Arg69Cys). This variant is present in population databases (rs377025174, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of mitochondrial complex III deficiency (PMID: 27959697, 31435670; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214160). 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%. Experimental studies have shown that this missense change affects BCS1L function (PMID: 31435670). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2024	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: 19508421, 17403714, 17314340, 12215968, 11528392, 31435670, 34662929, 27959697) -

Pili torti-deafness syndrome;C1864002:GRACILE syndrome;C3541471:Mitochondrial complex III deficiency nuclear type 1

Pathogenic:1Uncertain:1

Uncertain significance, flagged submission	clinical testing	Myriad Genetics, Inc.	Nov 01, 2021	NM_004328.4(BCS1L):c.205C>T(R69C) is a missense variant classified as a variant of uncertain significance in the context of BCS1L-related disorders. R69C has been observed in cases with relevant disease (PMID: 31435670, 30634555, 27959697). Functional assessments of this variant are available in the literature (PMID: 31435670). R69C has been observed in population frequency databases (gnomAD: FIN 0.03%). In summary, there is insufficient evidence to classify NM_004328.4(BCS1L):c.205C>T(R69C) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 11, 2024	- -

Pili torti-deafness syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 21, 2024

- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

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

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.55

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

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

1.6

.;.;.;L;L;L;.;L;L;L;L;.

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-3.1

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

REVEL

Pathogenic

0.68

Sift

Uncertain

0.014

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

Sift4G

Benign

0.11

T;T;T;D;D;D;T;D;D;D;D;.

Polyphen

0.98

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

Vest4

0.48, 0.49, 0.49, 0.45, 0.45

MVP

0.99

MPC

1.8

ClinPred

0.50

GERP RS

5.5

Varity_R

0.30

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over