VCV000156006.14 - ClinVar

NM_001370658.1(BTD):c.250-15del

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.

(6)

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_001370658.1(BTD):c.250-15del

Variation ID: 156006 Accession: VCV000156006.14

Type and length

Deletion, 1 bp

Location

Cytogenetic: 3p25.1 3: 15641893 (GRCh38) [ NCBI UCSC ] 3: 15683400 (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	Sep 22, 2014	Jun 17, 2024	Mar 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001370658.1:c.250-15del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001370658.1:c.250-15delT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_000060.3:c.310-15delT
NM_000060.4:c.310-15del
NM_001281723.4:c.250-15del		intron variant
NM_001281724.3:c.250-15del		intron variant
NM_001281725.3:c.250-15del		intron variant
NM_001281726.3:c.250-15del		intron variant
NM_001323582.2:c.250-15del		intron variant
NM_001370752.1:c.250-15del		intron variant
NM_001370753.1:c.250-15del		intron variant
NM_001407364.1:c.250-15del		intron variant
NM_001407365.1:c.250-15del		intron variant
NM_001407366.1:c.250-15del		intron variant
NM_001407367.1:c.250-15del		intron variant
NM_001407368.1:c.250-15del		intron variant
NM_001407369.1:c.250-15del		intron variant
NM_001407370.1:c.250-15del		intron variant
NM_001407371.1:c.250-15del		intron variant
NM_001407372.1:c.250-15del		intron variant
NM_001407373.1:c.250-15del		intron variant
NM_001407374.1:c.250-15del		intron variant
NM_001407375.1:c.250-15del		intron variant
NM_001407376.1:c.250-15del		intron variant
NM_001407377.1:c.250-15del		intron variant
NM_001407378.1:c.250-15del		intron variant
NM_001407379.1:c.250-15del		intron variant
NM_001407380.1:c.250-15del		intron variant
NM_001407381.1:c.313-15del		intron variant
NM_001407382.1:c.250-15del		intron variant
NM_001407383.1:c.250-15del		intron variant
NM_001407384.1:c.250-15del		intron variant
NM_001407386.1:c.250-15del		intron variant
NM_001407388.1:c.250-15del		intron variant
NM_001407390.1:c.250-15del		intron variant
NM_001407392.1:c.250-15del		intron variant
NM_001407394.1:c.250-15del		intron variant
NM_001407395.1:c.250-15del		intron variant
NM_001407396.1:c.250-15del		intron variant
NM_001407397.1:c.250-15del		intron variant
NM_001407398.1:c.250-15del		intron variant
NM_001407399.1:c.250-15del		intron variant
NM_001407400.1:c.250-15del		intron variant
NM_001407401.1:c.250-15del		intron variant
NC_000003.12:g.15641893del
NC_000003.11:g.15683400del
NG_008019.2:g.45542del
NG_008019.3:g.45543del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:15641892: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.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00005

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA278444 dbSNP: rs587783008 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.
BTD		-	-	GRCh38 GRCh37	670	756

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.
Biotinidase deficiency	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 1, 2024	RCV000144063.16

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 (Apr 13, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Biotinidase deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003929215.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (5) PubMed: 26810761‚ 25144890‚ 31801038‚ 24797656‚ 30912303 Comment: Variant summary: BTD c.250-15delT, also referred to as c.310-15delT, alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, … (more) Variant summary: BTD c.250-15delT, also referred to as c.310-15delT, alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant creates a 3' acceptor site, two predict the variant weakens a canonical 3' acceptor site, and one predicts the variant has no significant impact on splicing. However, a functional study found no evidence that the variant impacts splicing (Li_2014). The variant allele was found at a frequency of 8.3e-06 in 241528 control chromosomes (gnomAD). c.250-15delT has been reported in the literature in the compound heterozygous state in individuals affected with partial Biotinidase Deficiency, including at least one case where it was confirmed to be in trans with a pathogenic variant (e.g. Li_2014, Procter_2016, Carvalho_2019, Carvalho_2020). These data indicate that the variant may be associated with disease. Experimental evidence evaluating an impact of the variant found that although it does not appear to impact splicing, the variant may result in decreased mRNA expression (Li_2014). This study found that a patient who was compound heterozygous for the variant and the patient's mother, who was a heterozygous carrier, both exhibited decreased mRNA expression, approximately 40% and 65%, respectively, compared to control individuals. Three ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance, likely pathogenic and pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Pathogenic (Jan 22, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Biotinidase deficiency Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002151883.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 24797656‚ 26810761‚ 30912303‚ 17576681‚ 9536098 Comment: This sequence change falls in intron 2 of the BTD gene. It does not directly change the encoded amino acid sequence of the BTD protein. … (more) This sequence change falls in intron 2 of the BTD gene. It does not directly change the encoded amino acid sequence of the BTD protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs587783008, gnomAD 0.01%). This variant has been observed in individual(s) with biotinidase deficiency (PMID: 24797656, 26810761, 30912303). 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: 156006). Studies have shown that this variant alters BTD gene expression (PMID: 24797656). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Mar 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Biotinidase deficiency Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004211458.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Biotinidase deficiency Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001136338.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Biotinidase deficiency Affected status: yes Allele origin: germline	Molecular Genetics Diagnostic Laboratory, Detroit Medical Center University Laboratories Accession: SCV000189136.1 First in ClinVar: Sep 22, 2014 Last updated: Sep 22, 2014	Publications: PubMed (1) PubMed: 24797656 Number of individuals with the variant: 1
Uncertain significance (May 29, 2018)	Flagged submission flagged submission (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Biotinidase deficiency Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000800261.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 24797656‚ 26810761
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Variant summary: BTD c.250-15delT, also referred to as c.310-15delT, alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant creates a 3' acceptor site, two predict the variant weakens a canonical 3' acceptor site, and one predicts the variant has no significant impact on splicing. However, a functional study found no evidence that the variant impacts splicing (Li_2014). The variant allele was found at a frequency of 8.3e-06 in 241528 control chromosomes (gnomAD). c.250-15delT has been reported in the literature in the compound heterozygous state in individuals affected with partial Biotinidase Deficiency, including at least one case where it was confirmed to be in trans with a pathogenic variant (e.g. Li_2014, Procter_2016, Carvalho_2019, Carvalho_2020). These data indicate that the variant may be associated with disease. Experimental evidence evaluating an impact of the variant found that although it does not appear to impact splicing, the variant may result in decreased mRNA expression (Li_2014). This study found that a patient who was compound heterozygous for the variant and the patient's mother, who was a heterozygous carrier, both exhibited decreased mRNA expression, approximately 40% and 65%, respectively, compared to control individuals. Three ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance, likely pathogenic and pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

This sequence change falls in intron 2 of the BTD gene. It does not directly change the encoded amino acid sequence of the BTD protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs587783008, gnomAD 0.01%). This variant has been observed in individual(s) with biotinidase deficiency (PMID: 24797656, 26810761, 30912303). 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: 156006). Studies have shown that this variant alters BTD gene expression (PMID: 24797656). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified 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
Frequency of biotinidase gene variants and incidence of biotinidase deficiency in the Newborn Screening Program in Minas Gerais, Brazil.	Carvalho NO	Journal of medical screening	2020	PMID: 31801038
Novel mutations causing biotinidase deficiency in individuals identified by the newborn screening program in Minas Gerais, Brazil.	Carvalho NO	American journal of medical genetics. Part A	2019	PMID: 30912303
Forty-eight novel mutations causing biotinidase deficiency.	Procter M	Molecular genetics and metabolism	2016	PMID: 26810761
Outcomes of individuals with profound and partial biotinidase deficiency ascertained by newborn screening in Michigan over 25 years.	Jay AM	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25144890
Novel mutations causing biotinidase deficiency in individuals identified by newborn screening in Michigan including an unique intronic mutation that alters mRNA expression of the biotinidase gene.	Li H	Molecular genetics and metabolism	2014	PMID: 24797656
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs587783008 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001370658.1(BTD):c.250-15del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587783008 ...