VCV000006167.41 - ClinVar

NM_001079866.2(BCS1L):c.232A>G (p.Ser78Gly)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(15)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001079866.2(BCS1L):c.232A>G (p.Ser78Gly)

Variation ID: 6167 Accession: VCV000006167.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 218661219 (GRCh38) [ NCBI UCSC ] 2: 219525942 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 2, 2015	Oct 20, 2024	Dec 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001079866.2:c.232A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001073335.1:p.Ser78Gly	missense
NM_001257342.2:c.232A>G	NP_001244271.1:p.Ser78Gly	missense
NM_001257343.2:c.232A>G	NP_001244272.1:p.Ser78Gly	missense
NM_001257344.2:c.232A>G	NP_001244273.1:p.Ser78Gly	missense
NM_001318836.2:c.-40-187A>G		intron variant
NM_001320717.2:c.232A>G	NP_001307646.1:p.Ser78Gly	missense
NM_001371443.1:c.232A>G	NP_001358372.1:p.Ser78Gly	missense
NM_001371444.1:c.232A>G	NP_001358373.1:p.Ser78Gly	missense
NM_001371446.1:c.232A>G	NP_001358375.1:p.Ser78Gly	missense
NM_001371447.1:c.232A>G	NP_001358376.1:p.Ser78Gly	missense
NM_001371448.1:c.232A>G	NP_001358377.1:p.Ser78Gly	missense
NM_001371449.1:c.232A>G	NP_001358378.1:p.Ser78Gly	missense
NM_001371450.1:c.232A>G	NP_001358379.1:p.Ser78Gly	missense
NM_001371451.1:c.-40-187A>G		intron variant
NM_001371452.1:c.-41-540A>G		intron variant
NM_001371453.1:c.-245A>G		5 prime UTR
NM_001371454.1:c.-245A>G		5 prime UTR
NM_001371455.1:c.-245A>G		5 prime UTR
NM_001371456.1:c.-245A>G		5 prime UTR
NM_001374085.1:c.232A>G	NP_001361014.1:p.Ser78Gly	missense
NM_001374086.1:c.-245A>G		5 prime UTR
NM_004328.5:c.232A>G	NP_004319.1:p.Ser78Gly	missense
NR_163955.1:n.1244A>G		non-coding transcript variant
NC_000002.12:g.218661219A>G
NC_000002.11:g.219525942A>G
NG_008018.1:g.6564A>G
NG_033099.1:g.3322T>C
LRG_539:g.6564A>G
LRG_539t1:c.232A>G	LRG_539p1:p.Ser78Gly
	Q9Y276:p.Ser78Gly

... more HGVS ... less HGVS

Protein change

S78G

Other names

Canonical SPDI

NC_000002.12:218661218:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00005

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Exome Aggregation Consortium (ExAC) 0.00039

The Genome Aggregation Database (gnomAD) 0.00042

The Genome Aggregation Database (gnomAD), exomes 0.00047

Links

UniProtKB: Q9Y276#VAR_018149 OMIM: 603647.0005 dbSNP: rs28937590 ClinGen: CA118004 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BCS1L		-	-	GRCh38 GRCh37	492	530

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
GRACILE syndrome	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Dec 9, 2019	RCV000006542.23
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 29, 2023	RCV000519547.35
Mitochondrial complex III deficiency nuclear type 1	Pathogenic (1)	no assertion criteria provided	Jul 21, 2015	RCV000983982.8
GRACILE syndrome Mitochondrial complex III deficiency nuclear type 1 Pili torti-deafness syndrome	Pathogenic (1)	criteria provided, single submitter	Mar 12, 2022	RCV002476936.8
Pili torti-deafness syndrome	Pathogenic (1)	criteria provided, single submitter	Dec 24, 2023	RCV003472987.2
BCS1L-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 19, 2024	RCV004732532.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 14, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	GRACILE syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698304.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Publications: PubMed (2) PubMed: 12215968‚ 25914718 Comment: Variant summary: The BCS1L c.232A>G (p.Ser78Gly) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant … (more) Variant summary: The BCS1L c.232A>G (p.Ser78Gly) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 48/122498 control chromosomes at a frequency of 0.0003918, which does not exceed the estimated maximal expected allele frequency of a pathogenic BCS1L variant (0.0004725). Homozygotes of this variant have been reported exclusively in Finnish patients with GRACILE syndrome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Dec 09, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	GRACILE syndrome Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193863.1 First in ClinVar: Apr 06, 2020 Last updated: Apr 06, 2020	Publications: PubMed (2) PubMed: 12215968‚ 21274865 Comment: NM_004328.4(BCS1L):c.232A>G(S78G) is classified as pathogenic in the context of BCS1L-related disorders. Sources cited for classification include the following: PMID 12215968 and 21274865. Classification of NM_004328.4(BCS1L):c.232A>G(S78G) … (more) NM_004328.4(BCS1L):c.232A>G(S78G) is classified as pathogenic in the context of BCS1L-related disorders. Sources cited for classification include the following: PMID 12215968 and 21274865. Classification of NM_004328.4(BCS1L):c.232A>G(S78G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Mar 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial complex III deficiency nuclear type 1 Pili torti-deafness syndrome GRACILE syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893576.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Sep 26, 2014)	criteria provided, single submitter (Courtagen Life Sciences Classifications) Method: clinical testing	GRACILE syndrome Affected status: unknown Allele origin: germline	Courtagen Diagnostics Laboratory, Courtagen Life Sciences Accession: SCV000236535.2 First in ClinVar: Jul 02, 2015 Last updated: Jul 02, 2015
Pathogenic (Sep 08, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	GRACILE syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680154.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Sex: male Tissue: blood
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	GRACILE syndrome Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001162935.1 First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020
Pathogenic (Dec 09, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000617082.3 First in ClinVar: Dec 19, 2017 Last updated: Dec 17, 2022	Comment: Functional studies demonstrate that S78G is associated with decreased stability of the BCS1L protein (Visapaa et al., 2002); Transgenic mice with homozygosity for the S78G … (more) Functional studies demonstrate that S78G is associated with decreased stability of the BCS1L protein (Visapaa et al., 2002); Transgenic mice with homozygosity for the S78G variant demonstrate decreased BCS1L expression and decreased Rieske iron-sulfur protein incorporation into complex III (Davoudi et al., 2014); This variant is associated with the following publications: (PMID: 21274865, 27997587, 29782205, 28424480, 30530468, 22829922, 18386115, 31980526, 12547234, 27809283, 32637629, 34662929, 24466228, 12215968) (less)
Pathogenic (Dec 29, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001207152.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 12215968‚ 12547234‚ 18386115‚ 19508421‚ 21274865 Comment: This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 78 of the BCS1L protein (p.Ser78Gly). … (more) This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 78 of the BCS1L protein (p.Ser78Gly). This variant is present in population databases (rs28937590, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with clinical features of BCS1L-related conditions (PMID: 12215968, 12547234, 18386115, 19508421). It is commonly reported in individuals of Finnish ancestry (PMID: 12215968). ClinVar contains an entry for this variant (Variation ID: 6167). 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: 12215968, 21274865). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pili torti-deafness syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004210777.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Oct 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002064003.20 First in ClinVar: Jan 26, 2022 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Oct 01, 2002)	no assertion criteria provided Method: literature only	GRACILE SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026725.2 First in ClinVar: Apr 04, 2013 Last updated: Jan 20, 2017	Publications: PubMed (2) PubMed: 12215968‚ 11528392 Comment on evidence: Visapaa et al. (2002) reported that all GRACILE syndrome (603358) patients in Finland were homozygous for a 232A-G mutation in exon 2 of the BCS1L … (more) Visapaa et al. (2002) reported that all GRACILE syndrome (603358) patients in Finland were homozygous for a 232A-G mutation in exon 2 of the BCS1L gene, resulting in a ser78-to-gly (S78G) substitution. Unlike the Turkish patients reported by de Lonlay et al. (2001), the Finnish patients had normal complex III activity and no neurologic problems, but did have marked iron overload. (less)
Pathogenic (Mar 08, 2016)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes Accession: SCV000778193.1 First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018
Pathogenic (Jan 19, 2021)	no assertion criteria provided Method: clinical testing	GRACILE syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002076346.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
Pathogenic (Mar 19, 2024)	no assertion criteria provided Method: clinical testing	BCS1L-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005361188.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The BCS1L c.232A>G variant is predicted to result in the amino acid substitution p.Ser78Gly. This variant has been reported in the homozygous and compound heterozygous … (more) The BCS1L c.232A>G variant is predicted to result in the amino acid substitution p.Ser78Gly. This variant has been reported in the homozygous and compound heterozygous state in individuals with GRACILE syndrome (see, for example, Visapää et al. 2002. PubMed ID: 12215968 and Fellman et al. 2008. PubMed ID: 18386115). Transgenic mice homozygous for the p.Ser78Gly variant resemble the human syndrome with features including hepatopathy with progressive complex III deficiency and short lifespan (see for example Kotarsky et al. 2012. PubMed ID: 22829922). This variant is reported in 0.41% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/) and is interpreted as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6167/). Based on the available evidence, this variant is interpreted as pathogenic. (less)
Pathogenic (Jul 21, 2015)	no assertion criteria provided Method: clinical testing	Mitochondrial complex III deficiency nuclear type 1 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000678004.2 First in ClinVar: Jan 20, 2017 Last updated: Dec 23, 2019	Publications: PubMed (2) PubMed: 21274865‚ 12215968
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Comment:

Variant summary: The BCS1L c.232A>G (p.Ser78Gly) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 48/122498 control chromosomes at a frequency of 0.0003918, which does not exceed the estimated maximal expected allele frequency of a pathogenic BCS1L variant (0.0004725). Homozygotes of this variant have been reported exclusively in Finnish patients with GRACILE syndrome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

NM_004328.4(BCS1L):c.232A>G(S78G) is classified as pathogenic in the context of BCS1L-related disorders. Sources cited for classification include the following: PMID 12215968 and 21274865. Classification of NM_004328.4(BCS1L):c.232A>G(S78G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

Functional studies demonstrate that S78G is associated with decreased stability of the BCS1L protein (Visapaa et al., 2002); Transgenic mice with homozygosity for the S78G variant demonstrate decreased BCS1L expression and decreased Rieske iron-sulfur protein incorporation into complex III (Davoudi et al., 2014); This variant is associated with the following publications: (PMID: 21274865, 27997587, 29782205, 28424480, 30530468, 22829922, 18386115, 31980526, 12547234, 27809283, 32637629, 34662929, 24466228, 12215968)

Comment:

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 78 of the BCS1L protein (p.Ser78Gly). This variant is present in population databases (rs28937590, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with clinical features of BCS1L-related conditions (PMID: 12215968, 12547234, 18386115, 19508421). It is commonly reported in individuals of Finnish ancestry (PMID: 12215968). ClinVar contains an entry for this variant (Variation ID: 6167). 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: 12215968, 21274865). For these reasons, this variant has been classified as Pathogenic.

Comment:

The BCS1L c.232A>G variant is predicted to result in the amino acid substitution p.Ser78Gly. This variant has been reported in the homozygous and compound heterozygous state in individuals with GRACILE syndrome (see, for example, Visapää et al. 2002. PubMed ID: 12215968 and Fellman et al. 2008. PubMed ID: 18386115). Transgenic mice homozygous for the p.Ser78Gly variant resemble the human syndrome with features including hepatopathy with progressive complex III deficiency and short lifespan (see for example Kotarsky et al. 2012. PubMed ID: 22829922). This variant is reported in 0.41% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/) and is interpreted as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6167/). Based on the available evidence, this variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Nuclear gene mutations as the cause of mitochondrial complex III deficiency.	Fernández-Vizarra E	Frontiers in genetics	2015	PMID: 25914718
The GRACILE mutation introduced into Bcs1l causes postnatal complex III deficiency: a viable mouse model for mitochondrial hepatopathy.	Levéen P	Hepatology (Baltimore, Md.)	2011	PMID: 21274865
Clinical and biochemical spectrum of mitochondrial complex III deficiency caused by mutations in the BCS1L gene.	Ramos-Arroyo MA	Clinical genetics	2009	PMID: 19508421
Screening of BCS1L mutations in severe neonatal disorders suspicious for mitochondrial cause.	Fellman V	Journal of human genetics	2008	PMID: 18386115
The GRACILE syndrome, a neonatal lethal metabolic disorder with iron overload.	Fellman V	Blood cells, molecules & diseases	2002	PMID: 12547234
GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L.	Visapää I	American journal of human genetics	2002	PMID: 12215968
A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure.	de Lonlay P	Nature genetics	2001	PMID: 11528392

Text-mined citations for rs28937590 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001079866.2(BCS1L):c.232A>G (p.Ser78Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28937590 ...