VCV002581363.2 - ClinVar

NM_001079866.2(BCS1L):c.1A>T (p.Met1Leu)

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.

(2)

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/Likely 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.1A>T (p.Met1Leu)

Variation ID: 2581363 Accession: VCV002581363.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 218660988 (GRCh38) [ NCBI UCSC ] 2: 219525711 (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	Oct 7, 2023	Feb 20, 2024	Aug 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001079866.2:c.1A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001073335.1:p.Met1Leu	missense initiator codon variant
NM_001257342.2:c.1A>T	NP_001244271.1:p.Met1Leu	missense initiator codon variant
NM_001257343.2:c.1A>T	NP_001244272.1:p.Met1Leu	missense initiator codon variant
NM_001257344.2:c.1A>T	NP_001244273.1:p.Met1Leu	missense initiator codon variant
NM_001318836.2:c.-40-418A>T		intron variant
NM_001320717.2:c.1A>T	NP_001307646.1:p.Met1Leu	missense initiator codon variant
NM_001371443.1:c.1A>T	NP_001358372.1:p.Met1Leu	missense initiator codon variant
NM_001371444.1:c.1A>T	NP_001358373.1:p.Met1Leu	missense initiator codon variant
NM_001371446.1:c.1A>T	NP_001358375.1:p.Met1Leu	missense initiator codon variant
NM_001371447.1:c.1A>T	NP_001358376.1:p.Met1Leu	missense initiator codon variant
NM_001371448.1:c.1A>T	NP_001358377.1:p.Met1Leu	missense initiator codon variant
NM_001371449.1:c.1A>T	NP_001358378.1:p.Met1Leu	missense initiator codon variant
NM_001371450.1:c.1A>T	NP_001358379.1:p.Met1Leu	missense initiator codon variant
NM_001371451.1:c.-41+240A>T		intron variant
NM_001371452.1:c.-41-771A>T		intron variant
NM_001371453.1:c.-476A>T		5 prime UTR
NM_001371454.1:c.-476A>T		5 prime UTR
NM_001371455.1:c.-476A>T		5 prime UTR
NM_001371456.1:c.-476A>T		5 prime UTR
NM_001374085.1:c.1A>T	NP_001361014.1:p.Met1Leu	missense initiator codon variant
NM_001374086.1:c.-476A>T		5 prime UTR
NM_004328.5:c.1A>T	NP_004319.1:p.Met1Leu	missense initiator codon variant
NR_163955.1:n.1013A>T		non-coding transcript variant
NC_000002.12:g.218660988A>T
NC_000002.11:g.219525711A>T
NG_008018.1:g.6333A>T
NG_033099.1:g.3553T>A
NG_033099.2:g.3635T>A
LRG_539:g.6333A>T
LRG_539t1:c.1A>T	LRG_539p1:p.Met1Leu
LRG_539t2:c.1A>T	LRG_539p2:p.Met1Leu

... more HGVS ... less HGVS

Protein change

M1L

Other names

Canonical SPDI

NC_000002.12:218660987:A:T

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

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	Likely pathogenic (1)	criteria provided, single submitter	Aug 3, 2023	RCV003331768.1
not provided	Pathogenic (1)	criteria provided, single submitter	Aug 24, 2023	RCV003669387.2

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.
Likely pathogenic (Aug 03, 2023)	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: SCV004039398.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Comment: Variant summary: BCS1L c.1A>T (p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded … (more) Variant summary: BCS1L c.1A>T (p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The downstream second Met is located at codon 48. The variant was absent in 249840 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1A>T in individuals affected with GRACILE Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. In addition, variants upstream Met48 have been found in patients in HGMD and have been classified as pathogenic in ClinVar database, including c.1A.G (p.Met1Val). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Pathogenic (Aug 24, 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: SCV004385782.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28322498 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BCS1L protein in which other variant(s) (p.Arg45His) have … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BCS1L protein in which other variant(s) (p.Arg45His) have been determined to be pathogenic (PMID: 28322498). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with BCS1L-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the BCS1L mRNA. The next in-frame methionine is located at codon 48. (less)

Comment:

Variant summary: BCS1L c.1A>T (p.Met1Leu) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The downstream second Met is located at codon 48. The variant was absent in 249840 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1A>T in individuals affected with GRACILE Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. In addition, variants upstream Met48 have been found in patients in HGMD and have been classified as pathogenic in ClinVar database, including c.1A.G (p.Met1Val). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BCS1L protein in which other variant(s) (p.Arg45His) have been determined to be pathogenic (PMID: 28322498). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with BCS1L-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the BCS1L mRNA. The next in-frame methionine is located at codon 48.

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
Novel compound heterozygous mutations in BCS1L gene causing Bjornstad syndrome in two siblings.	Falco M	American journal of medical genetics. Part A	2017	PMID: 28322498

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001079866.2(BCS1L):c.1A>T (p.Met1Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...