NM_001370658.1(BTD):c.695A>G (p.Asp232Gly) AND Biotinidase deficiency

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Nov 13, 2023
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:: RCV000001978.18

Allele description [Variation Report for NM_001370658.1(BTD):c.695A>G (p.Asp232Gly)]

NM_001370658.1(BTD):c.695A>G (p.Asp232Gly)

Gene:

BTD:biotinidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.1

Genomic location:

Preferred name:

NM_001370658.1(BTD):c.695A>G (p.Asp232Gly)

Other names:

D252G

HGVS:

NC_000003.12:g.15644611A>G
NG_008019.2:g.48260A>G
NG_008019.3:g.48261A>G
NM_000060.4:c.755A>G
NM_001281723.4:c.695A>G
NM_001281724.3:c.695A>G
NM_001281725.3:c.695A>G
NM_001323582.2:c.695A>G
NM_001370658.1:c.695A>GMANE SELECT
NM_001370752.1:c.695A>G
NM_001370753.1:c.399+2554A>G
NM_001407364.1:c.695A>G
NM_001407365.1:c.695A>G
NM_001407366.1:c.695A>G
NM_001407367.1:c.695A>G
NM_001407368.1:c.695A>G
NM_001407369.1:c.695A>G
NM_001407370.1:c.695A>G
NM_001407371.1:c.695A>G
NM_001407372.1:c.695A>G
NM_001407373.1:c.695A>G
NM_001407374.1:c.695A>G
NM_001407375.1:c.695A>G
NM_001407376.1:c.695A>G
NM_001407377.1:c.695A>G
NM_001407378.1:c.695A>G
NM_001407379.1:c.695A>G
NP_000051.1:p.Asp252Gly
NP_001268652.2:p.Asp232Gly
NP_001268652.2:p.Asp232Gly
NP_001268653.2:p.Asp232Gly
NP_001268654.1:p.Asp232Gly
NP_001268654.1:p.Asp232Gly
NP_001310511.1:p.Asp232Gly
NP_001310511.1:p.Asp232Gly
NP_001357587.1:p.Asp232Gly
NP_001357681.1:p.Asp232Gly
NP_001394293.1:p.Asp232Gly
NP_001394294.1:p.Asp232Gly
NP_001394295.1:p.Asp232Gly
NP_001394296.1:p.Asp232Gly
NP_001394297.1:p.Asp232Gly
NP_001394298.1:p.Asp232Gly
NP_001394299.1:p.Asp232Gly
NP_001394300.1:p.Asp232Gly
NP_001394301.1:p.Asp232Gly
NP_001394302.1:p.Asp232Gly
NP_001394303.1:p.Asp232Gly
NP_001394304.1:p.Asp232Gly
NP_001394305.1:p.Asp232Gly
NP_001394306.1:p.Asp232Gly
NP_001394307.1:p.Asp232Gly
NP_001394308.1:p.Asp232Gly
NC_000003.11:g.15686118A>G
NM_001281723.3:c.695A>G
NM_001281723.3:c.695A>G
NM_001281725.2:c.695A>G
NM_001323582.1:c.695A>G

Protein change:

D232G; ASP252GLY

Links:

OMIM: 609019.0006; dbSNP: rs28934601

NCBI 1000 Genomes Browser:

rs28934601

Molecular consequence:

NM_001370753.1:c.399+2554A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000060.4:c.755A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281723.4:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281724.3:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001281725.3:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001323582.2:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001370658.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001370752.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407364.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407365.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407366.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407367.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407368.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407369.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407370.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407371.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407372.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407373.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407374.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407375.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407376.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407377.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407378.1:c.695A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001407379.1:c.695A>G - 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
SCV000022136	OMIM	no assertion criteria provided	Pathogenic (Nov 28, 1997)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000833941	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 13, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22698809, 26810761, 27629047, 27657684, 28498829, 28492532
SCV000894299	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193864	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 9, 2019)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10400129, 25174816, 15060693, 22698809, 26361991 Citation Link,
SCV001461220	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004040977	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 3, 2023)	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	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
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

Profound biotinidase deficiency in two asymptomatic adults.

Wolf B, Norrgard K, Pomponio RJ, Mock DM, McVoy JR, Fleischhauer K, Shapiro S, Blitzer MG, Hymes J.

Am J Med Genet. 1997 Nov 28;73(1):5-9.

PubMed [citation]

PMID:: 9375914

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

See all PubMed Citations (12)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000022136.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In an asymptomatic woman with biotinidase deficiency (253260) who was diagnosed after her child was identified by newborn screening, Wolf et al. (1997) identified a homozygous 755A-G transition, resulting in an asp252-to-gly (D252G) substitution. Her parents were heterozygous for the mutation. Her husband was heterozygous for a missense mutation (Q456H; 609019.0007). The enzyme-deficient daughter was a compound heterozygote for the mutations found in the mother and father. The son, who was identified through newborn screening, was presumably also a compound heterozygote for these 2 mutations.

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

From Invitae, SCV000833941.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 252 of the BTD protein (p.Asp252Gly). This variant is present in population databases (rs28934601, gnomAD 0.009%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 22698809, 26810761, 27629047, 27657684, 28498829). ClinVar contains an entry for this variant (Variation ID: 1901). 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%. 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 Fulgent Genetics, Fulgent Genetics, SCV000894299.1

#	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 Myriad Genetics, Inc., SCV001193864.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

NM_000060.2(BTD):c.755A>G(D252G) is classified as pathogenic in the context of biotinidase deficiency and is seen in patients with both partial and profound biotinidase deficiency. Sources cited for classification include the following: PMID 10400129, 25174816, 15060693, 22698809 and 26361991. Classification of NM_000060.2(BTD):c.755A>G(D252G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	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 Natera, Inc., SCV001461220.1

#	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, SCV004040977.1

#	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

Last Updated: Feb 20, 2024

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