NM_001370658.1(BTD):c.-17+2T>C AND Biotinidase deficiency

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Mar 2, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001379913.8

Allele description [Variation Report for NM_001370658.1(BTD):c.-17+2T>C]

NM_001370658.1(BTD):c.-17+2T>C

Gene:

BTD:biotinidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.1

Genomic location:

Preferred name:

NM_001370658.1(BTD):c.-17+2T>C

HGVS:

NC_000003.12:g.15601896T>C
NG_008019.3:g.5546T>C
NG_098817.1:g.523T>C
NM_000060.4:c.44+2T>C
NM_001281724.3:c.-205+2T>C
NM_001281726.3:c.-17+2T>C
NM_001323582.2:c.-293+2T>C
NM_001370658.1:c.-17+2T>CMANE SELECT
NM_001370752.1:c.-17+2T>C
NM_001370753.1:c.-17+2T>C
NM_001407365.1:c.-17+249T>C
NM_001407366.1:c.-582+2T>C
NM_001407369.1:c.-568+2T>C
NM_001407370.1:c.-569+126T>C
NM_001407371.1:c.-743+126T>C
NM_001407372.1:c.-174+2T>C
NM_001407373.1:c.-136+2T>C
NM_001407374.1:c.-191+2T>C
NM_001407378.1:c.-394+2T>C
NM_001407380.1:c.-17+2T>C
NM_001407384.1:c.-293+2T>C
NM_001407390.1:c.-191+2T>C
NM_001407394.1:c.-293+126T>C
NM_001407395.1:c.-132+2T>C
NM_001407398.1:c.-17+2T>C
NM_001407400.1:c.-17+2T>C
NC_000003.11:g.15643403T>C
NG_008019.2:g.5545T>C
NM_001370658.1:c.-17+2T>C

Links:

dbSNP: rs745648160

NCBI 1000 Genomes Browser:

rs745648160

Molecular consequence:

NM_001407365.1:c.-17+249T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001407370.1:c.-569+126T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001407371.1:c.-743+126T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001407394.1:c.-293+126T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001281724.3:c.-205+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001281726.3:c.-17+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001323582.2:c.-293+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370658.1:c.-17+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370752.1:c.-17+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001370753.1:c.-17+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407366.1:c.-582+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407369.1:c.-568+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407372.1:c.-174+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407373.1:c.-136+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407374.1:c.-191+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407378.1:c.-394+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407380.1:c.-17+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407384.1:c.-293+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407390.1:c.-191+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407395.1:c.-132+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407398.1:c.-17+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407400.1:c.-17+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Biotinidase deficiency
Synonyms:: BTD deficiency; Late-onset biotin-responsive multiple carboxylase deficiency; Biotin deficiency
Identifiers:: MONDO: MONDO:0009665; MedGen: C0220754; Orphanet: 79241; OMIM: 253260

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001577813	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 19, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16199547, 20083419, 28492532
SCV002081542	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Jun 15, 2017)	germline	clinical testing
SCV002511630	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 5, 2022)	germline	clinical testing	Citation Link,
SCV002811539	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 10, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004211387	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 2, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

The identification of novel mutations in the biotinidase gene using denaturing high pressure liquid chromatography (dHPLC).

Iqbal F, Item CB, Vilaseca MA, Jalan A, Mühl A, Couce ML, Duat A, Delgado MP, Bosch J, Puche A, Campistol J, Pineda M, Bodamer OA.

Mol Genet Metab. 2010 May;100(1):42-5. doi: 10.1016/j.ymgme.2009.12.016. Epub 2010 Jan 4.

PubMed [citation]

PMID:: 20083419

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001577813.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change affects a donor splice site in intron 1 of the BTD gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs745648160, ExAC 0.05%). This variant has not been reported in the literature in individuals with BTD-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BTD are known to be pathogenic (PMID: 20083419). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002081542.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511630.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: BTD c.-17+2T>C is located in a splice-site region of the non-coding exon 1, upstream of the initiation codon, and is predicted by multiple computational tools to abolish the canonical 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 249782 control chromosomes (gnomAD). To our knowledge, no occurrence of c.-17+2T>C in individuals affected with Biotinidase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. While expression of exon 1 is absent in most tissues in the GTEx database, and it is a non-coding exon in the transcript utilized in this classification, there is evidence that exon 1 remains an important region of the gene. Another variant which impacts the same splice-site, c.-17+1G>A, has been reported in a patient affected with partial Biotinidase Deficiency (PMID 29728376) and is cited in ClinVar as likely pathogenic. Additionally, a 107-kb contiguous deletion of three genes in homozygosity, including exon 1 of the BTD gene, has been reported in a child whose symptoms were apparently solely attributable to the BTD gene and improved with biotin supplementation (PMID 28649532). The authors of this study concluded that deletion of exon 1 results in the inability to synthesize the active enzyme product, as exon 1 contains the initiation site and leader signal sequence of the enzyme, supporting a critical role for this exon, with the caveat that a deletion of the region may have a different impact than a variant affecting splicing (PMID 28649532). A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002811539.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004211387.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 1, 2024

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