VCV000056411.6 - ClinVar

NM_001079866.2(BCS1L):c.-49-539T>A

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

2 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001079866.2(BCS1L):c.-49-539T>A

Variation ID: 56411 Accession: VCV000056411.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 218660400 (GRCh38) [ NCBI UCSC ] 2: 219525123 (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	Aug 21, 2013	Jun 29, 2025	Jun 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001079866.2:c.-49-539T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001257342.2:c.-50+234T>A		intron variant
NM_001257343.2:c.-50+182T>A		intron variant
NM_001257344.2:c.-49-539T>A		intron variant
NM_001318836.2:c.-41+657T>A		intron variant
NM_001320717.2:c.-71T>A		5 prime UTR
NM_001371443.1:c.-71T>A		5 prime UTR
NM_001371444.1:c.-71T>A		5 prime UTR
NM_001371446.1:c.-398T>A		5 prime UTR
NM_001371447.1:c.-31-557T>A		intron variant
NM_001371448.1:c.-71T>A		5 prime UTR
NM_001371449.1:c.-71T>A		5 prime UTR
NM_001371450.1:c.-71T>A		5 prime UTR
NM_001371451.1:c.-389T>A		5 prime UTR
NM_001371452.1:c.-42+657T>A		intron variant
NM_001371453.1:c.-1064T>A		5 prime UTR
NM_001371454.1:c.-547T>A		5 prime UTR
NM_001371455.1:c.-525-539T>A		intron variant
NM_001371456.1:c.-526+234T>A		intron variant
NM_001374085.1:c.-588T>A		5 prime UTR
NM_001374086.1:c.-1064T>A		5 prime UTR
NM_004328.5:c.-50+155T>A		intron variant
NR_163955.1:n.425T>A		non-coding transcript variant
NC_000002.12:g.218660400T>A
NC_000002.11:g.219525123T>A
NG_008018.1:g.5745T>A
NG_033099.1:g.4141A>T
LRG_539:g.5745T>A
LRG_539t1:c.-50+155T>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:218660399:T:A

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.

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

Links

ClinGen: CA144343 dbSNP: rs386833855 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		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	541	579

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	Conflicting classifications of pathogenicity (2)	no assertion criteria provided	Jun 7, 2018	RCV000049824.3
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jun 18, 2023	RCV003556129.3
not specified	Uncertain significance (1)	criteria provided, single submitter	Jun 24, 2024	RCV004700349.1

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.
Uncertain significance (Jun 24, 2024) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005205528.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Publications: PubMed (2) PubMed: 12215968‚ 22277166 Comment: Variant summary: BCS1L c.-50+155T>A is located in the untranslated mRNA region upstream of the initiation codon. The frequency of this variant in the general population … (more) Variant summary: BCS1L c.-50+155T>A is located in the untranslated mRNA region upstream of the initiation codon. The frequency of this variant in the general population could not be determined as the technology used for large population databases (ExAC, gnomAD, ESP, 1000G) cannot detect variants of this type. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-50+155T>A has been reported in the literature in hte compound heterozygous state in individuals affected with GRACILE Syndrome (e.g. Vispaa_2002, Lynn_2012). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant is also known as c.-588T>A. The following publications have been ascertained in the context of this evaluation (PMID: 22277166, 12215968). ClinVar contains an entry for this variant (Variation ID: 56411). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)

Likely pathogenic (Jun 18, 2023) C Contributing to aggregate classification	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: SCV004293969.2 First in ClinVar: Feb 14, 2024 Last updated: Mar 04, 2025	Publications: PubMed (2) PubMed: 12215968‚ 22277166 Comment: This variant is also known as c.-588T>A. This variant occurs in a non-coding region of the BCS1L gene. It does not change the encoded amino … (more) This variant is also known as c.-588T>A. This variant occurs in a non-coding region of the BCS1L gene. It does not change the encoded amino acid sequence of the BCS1L protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with GRACILE syndrome (PMID: 12215968, 22277166). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56411). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: not provided	GRACILE syndrome Affected status: not provided Allele origin: unknown	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) Accession: SCV000082233.2 First in ClinVar: Aug 21, 2013 Last updated: Jun 08, 2025 Comment: FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference	Comment: Converted during submission from probable-pathogenic to Likely pathogenic.

Uncertain significance (Jun 07, 2018) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	GRACILE syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000800718.2 First in ClinVar: Aug 21, 2013 Last updated: Jun 29, 2025	Publications: PubMed (2) PubMed: 22277166‚ 12215968 Comment: This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Comment:

Variant summary: BCS1L c.-50+155T>A is located in the untranslated mRNA region upstream of the initiation codon. The frequency of this variant in the general population could not be determined as the technology used for large population databases (ExAC, gnomAD, ESP, 1000G) cannot detect variants of this type. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-50+155T>A has been reported in the literature in hte compound heterozygous state in individuals affected with GRACILE Syndrome (e.g. Vispaa_2002, Lynn_2012). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant is also known as c.-588T>A. The following publications have been ascertained in the context of this evaluation (PMID: 22277166, 12215968). ClinVar contains an entry for this variant (Variation ID: 56411). Based on the evidence outlined above, the variant was classified as uncertain significance.

Comment:

This variant is also known as c.-588T>A. This variant occurs in a non-coding region of the BCS1L gene. It does not change the encoded amino acid sequence of the BCS1L protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with GRACILE syndrome (PMID: 12215968, 22277166). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56411). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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
BCS1L gene mutation presenting with GRACILE-like syndrome and complex III deficiency.	Lynn AM	Annals of clinical biochemistry	2012	PMID: 22277166
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

Text-mined citations for rs386833855 ...

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 Jul 05, 2025

ClinVar Genomic variation as it relates to human health

NM_001079866.2(BCS1L):c.-49-539T>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs386833855 ...