NM_001370658.1(BTD):c.1309G>T (p.Val437Leu) AND Biotinidase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 21, 2023
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:: RCV000665732.4

Allele description [Variation Report for NM_001370658.1(BTD):c.1309G>T (p.Val437Leu)]

NM_001370658.1(BTD):c.1309G>T (p.Val437Leu)

Gene:

BTD:biotinidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.1

Genomic location:

Preferred name:

NM_001370658.1(BTD):c.1309G>T (p.Val437Leu)

HGVS:

NC_000003.12:g.15645225G>T
NG_008019.2:g.48874G>T
NG_008019.3:g.48875G>T
NM_000060.4:c.1369G>T
NM_001281723.4:c.1309G>T
NM_001281724.3:c.1309G>T
NM_001281725.3:c.1309G>T
NM_001323582.2:c.1309G>T
NM_001370658.1:c.1309G>TMANE SELECT
NM_001370752.1:c.1015+294G>T
NM_001370753.1:c.399+3168G>T
NM_001407364.1:c.1309G>T
NM_001407365.1:c.1309G>T
NM_001407366.1:c.1309G>T
NM_001407367.1:c.1309G>T
NM_001407368.1:c.1309G>T
NM_001407369.1:c.1309G>T
NM_001407370.1:c.1309G>T
NM_001407371.1:c.1309G>T
NM_001407372.1:c.1309G>T
NM_001407373.1:c.1309G>T
NM_001407374.1:c.1309G>T
NM_001407375.1:c.1309G>T
NM_001407376.1:c.1309G>T
NM_001407377.1:c.1309G>T
NM_001407378.1:c.1309G>T
NP_000051.1:p.Val457Leu
NP_001268652.2:p.Val437Leu
NP_001268652.2:p.Val437Leu
NP_001268653.2:p.Val437Leu
NP_001268654.1:p.Val437Leu
NP_001268654.1:p.Val437Leu
NP_001310511.1:p.Val437Leu
NP_001310511.1:p.Val437Leu
NP_001357587.1:p.Val437Leu
NP_001394293.1:p.Val437Leu
NP_001394294.1:p.Val437Leu
NP_001394295.1:p.Val437Leu
NP_001394296.1:p.Val437Leu
NP_001394297.1:p.Val437Leu
NP_001394298.1:p.Val437Leu
NP_001394299.1:p.Val437Leu
NP_001394300.1:p.Val437Leu
NP_001394301.1:p.Val437Leu
NP_001394302.1:p.Val437Leu
NP_001394303.1:p.Val437Leu
NP_001394304.1:p.Val437Leu
NP_001394305.1:p.Val437Leu
NP_001394306.1:p.Val437Leu
NP_001394307.1:p.Val437Leu
NC_000003.11:g.15686732G>T
NM_001281723.3:c.1309G>T
NM_001281725.2:c.1309G>T
NM_001323582.1:c.1309G>T

Protein change:

V437L

Links:

dbSNP: rs146600671

NCBI 1000 Genomes Browser:

rs146600671

Molecular consequence:

NM_001370752.1:c.1015+294G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001370753.1:c.399+3168G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000060.4:c.1369G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281723.4:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281724.3:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001281725.3:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001323582.2:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001370658.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407364.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407365.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407366.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407367.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407368.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407369.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407370.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407371.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407372.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407373.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407374.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407375.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407376.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407377.1:c.1309G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001407378.1:c.1309G>T - 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
SCV000789899	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Mar 13, 2017)	unknown	clinical testing	Citation Link,
SCV004627586	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 21, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9396567, 28281033, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000789899

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Mar 13, 2017)

unknown

clinical testing

Citation Link,

SCV004627586

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 21, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Mutations in the human biotinidase gene that cause profound biotinidase deficiency in symptomatic children: molecular, biochemical, and clinical analysis.

Pomponio RJ, Hymes J, Reynolds TR, Meyers GA, Fleischhauer K, Buck GA, Wolf B.

Pediatr Res. 1997 Dec;42(6):840-8.

PubMed [citation]

PMID:: 9396567

A treatable cause of myelopathy and vision loss mimicking neuromyelitis optica spectrum disorder: late-onset biotinidase deficiency.

Yilmaz S, Serin M, Canda E, Eraslan C, Tekin H, Ucar SK, Gokben S, Tekgul H, Serdaroglu G.

Metab Brain Dis. 2017 Jun;32(3):675-678. doi: 10.1007/s11011-017-9984-5. Epub 2017 Mar 9.

PubMed [citation]

PMID:: 28281033

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000789899.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004627586.1

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

Description

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. This variant disrupts the p.Val457 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9396567, 28281033). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 550861). This variant has not been reported in the literature in individuals affected with BTD-related conditions. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 457 of the BTD protein (p.Val457Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%).

#	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

Last Updated: Sep 29, 2024

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