NM_001370658.1(BTD):c.1372G>A (p.Ala458Thr) AND Biotinidase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Mar 29, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000022034.12

Allele description [Variation Report for NM_001370658.1(BTD):c.1372G>A (p.Ala458Thr)]

NM_001370658.1(BTD):c.1372G>A (p.Ala458Thr)

Gene:

BTD:biotinidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.1

Genomic location:

Preferred name:

NM_001370658.1(BTD):c.1372G>A (p.Ala458Thr)

HGVS:

NC_000003.12:g.15645288G>A
NG_008019.2:g.48937G>A
NG_008019.3:g.48938G>A
NM_000060.4:c.1432G>A
NM_001281723.4:c.1372G>A
NM_001281724.3:c.1372G>A
NM_001281725.3:c.1372G>A
NM_001323582.2:c.1372G>A
NM_001370658.1:c.1372G>AMANE SELECT
NM_001370752.1:c.1015+357G>A
NM_001370753.1:c.399+3231G>A
NM_001407364.1:c.1372G>A
NM_001407365.1:c.1372G>A
NM_001407366.1:c.1372G>A
NM_001407367.1:c.1372G>A
NM_001407368.1:c.1372G>A
NM_001407369.1:c.1372G>A
NM_001407370.1:c.1372G>A
NM_001407371.1:c.1372G>A
NM_001407372.1:c.1372G>A
NM_001407373.1:c.1372G>A
NM_001407374.1:c.1372G>A
NM_001407375.1:c.1372G>A
NM_001407376.1:c.1372G>A
NM_001407377.1:c.1372G>A
NM_001407378.1:c.1372G>A
NP_000051.1:p.Ala478Thr
NP_001268652.2:p.Ala458Thr
NP_001268652.2:p.Ala458Thr
NP_001268653.2:p.Ala458Thr
NP_001268654.1:p.Ala458Thr
NP_001268654.1:p.Ala458Thr
NP_001310511.1:p.Ala458Thr
NP_001310511.1:p.Ala458Thr
NP_001357587.1:p.Ala458Thr
NP_001394293.1:p.Ala458Thr
NP_001394294.1:p.Ala458Thr
NP_001394295.1:p.Ala458Thr
NP_001394296.1:p.Ala458Thr
NP_001394297.1:p.Ala458Thr
NP_001394298.1:p.Ala458Thr
NP_001394299.1:p.Ala458Thr
NP_001394300.1:p.Ala458Thr
NP_001394301.1:p.Ala458Thr
NP_001394302.1:p.Ala458Thr
NP_001394303.1:p.Ala458Thr
NP_001394304.1:p.Ala458Thr
NP_001394305.1:p.Ala458Thr
NP_001394306.1:p.Ala458Thr
NP_001394307.1:p.Ala458Thr
NC_000003.11:g.15686795G>A
NM_001281723.3:c.1372G>A
NM_001281725.2:c.1372G>A
NM_001323582.1:c.1372G>A
NM_001370658.1:c.1372G>A

Protein change:

A458T

Links:

dbSNP: rs181396238

NCBI 1000 Genomes Browser:

rs181396238

Molecular consequence:

NM_001370752.1:c.1015+357G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001370753.1:c.399+3231G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000060.4:c.1432G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281723.4:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281724.3:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001281725.3:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323582.2:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001370658.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407364.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407365.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407366.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407367.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407368.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407369.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407370.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407371.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407372.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407373.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407374.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407375.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407376.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407377.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407378.1:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000800692	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Apr 12, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000963906	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26810761, 19757147, 28492532
SCV001461226	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV004211395	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 29, 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

Forty-eight novel mutations causing biotinidase deficiency.

Procter M, Wolf B, Mao R.

Mol Genet Metab. 2016 Mar;117(3):369-72. doi: 10.1016/j.ymgme.2016.01.002. Epub 2016 Jan 12.

PubMed [citation]

PMID:: 26810761

High incidence of profound biotinidase deficiency detected in newborn screening blood spots in the Somalian population in Minnesota.

Sarafoglou K, Bentler K, Gaviglio A, Redlinger-Grosse K, Anderson C, McCann M, Bloom B, Babovic-Vuksanovic D, Gavrilov D, Berry SA.

J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S169-73. doi: 10.1007/s10545-009-1135-7. Epub 2009 Sep 7.

PubMed [citation]

PMID:: 19757147

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000800692.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000963906.4

#	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 replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 478 of the BTD protein (p.Ala478Thr). This variant is present in population databases (rs181396238, gnomAD 0.01%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 26810761). ClinVar contains an entry for this variant (Variation ID: 25108). 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 BTD protein function with a positive predictive value of 95%. This variant disrupts the p.Ala478 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 19757147), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as 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., SCV001461226.1

#	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 Baylor Genetics, SCV004211395.2

#	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: Oct 8, 2024

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