NM_001370658.1(BTD):c.641C>T (p.Thr214Ile) AND Biotinidase deficiency

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 24, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000144060.3

Allele description [Variation Report for NM_001370658.1(BTD):c.641C>T (p.Thr214Ile)]

NM_001370658.1(BTD):c.641C>T (p.Thr214Ile)

Gene:
BTD:biotinidase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.1
Genomic location:
Preferred name:
NM_001370658.1(BTD):c.641C>T (p.Thr214Ile)
HGVS:
  • NC_000003.12:g.15644557C>T
  • NG_008019.1:g.47810C>T
  • NG_008019.2:g.48206C>T
  • NM_000060.2:c.701C>T
  • NM_001281723.3:c.641C>T
  • NM_001281724.3:c.641C>T
  • NM_001281725.2:c.641C>T
  • NM_001323582.1:c.641C>T
  • NM_001370658.1:c.641C>TMANE SELECT
  • NM_001370752.1:c.641C>T
  • NM_001370753.1:c.399+2500C>T
  • NP_001268652.2:p.Thr214Ile
  • NP_001268653.2:p.Thr214Ile
  • NP_001268654.1:p.Thr214Ile
  • NP_001310511.1:p.Thr214Ile
  • NP_001357587.1:p.Thr214Ile
  • NP_001357681.1:p.Thr214Ile
  • NC_000003.11:g.15686064C>T
Protein change:
T214I
Links:
dbSNP: rs587783005
NCBI 1000 Genomes Browser:
rs587783005
Molecular consequence:
  • NM_001370753.1:c.399+2500C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001281723.3:c.641C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281724.3:c.641C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281725.2:c.641C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001323582.1:c.641C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370658.1:c.641C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370752.1:c.641C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000189133Molecular Genetics Diagnostic Laboratory,Detroit Medical Center University Laboratoriesno assertion criteria providedPathogenicgermlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000845814Research and Development, ARUP Laboratoriesno assertion criteria providedPathogenic
(Feb 17, 2017)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000915027Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely pathogenic
(Oct 9, 2017)
germlineclinical testing

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

Citation Link,

SCV000933006Invitaecriteria provided, single submitter
Pathogenic
(Oct 24, 2018)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenonot providednot providednot providednot providednot providedliterature only
not providedgermlineyes2not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Outcomes of individuals with profound and partial biotinidase deficiency ascertained by newborn screening in Michigan over 25 years.

Jay AM, Conway RL, Feldman GL, Nahhas F, Spencer L, Wolf B.

Genet Med. 2015 Mar;17(3):205-9. doi: 10.1038/gim.2014.104. Epub 2014 Aug 21.

PubMed [citation]
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, Spencer L, Nahhas F, Miller J, Fribley A, Feldman G, Conway R, Wolf B.

Mol Genet Metab. 2014 Jul;112(3):242-6. doi: 10.1016/j.ymgme.2014.04.002. Epub 2014 Apr 16.

PubMed [citation]
PMID:
24797656
See all PubMed Citations (4)

Details of each submission

From Molecular Genetics Diagnostic Laboratory,Detroit Medical Center University Laboratories, SCV000189133.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided2not providednot providednot provided

From Research and Development, ARUP Laboratories, SCV000845814.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

Enzyme activities @ 2.3 U/L with c.1330G>C;p.D444H in one patient. Enzyme activity @ 0.8 U/L in a homozygous patient.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000915027.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

The BTD c.701C>T (p.Thr234Ile) missense variant has been reported in at least three individuals, including in a homozygous state in one individual with profound biotinidase deficiency, and in a compound heterozygous state in two individuals, including one with profound and one with partial biotinidase deficiency (Li et al. 2014; Wolf et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.00026 in the South Asian population of the Genome Aggregation Database. Based on the evidence, the p.Thr234Ile variant is classified as likely pathogenic for biotinidase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000933006.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces threonine with isoleucine at codon 234 of the BTD protein (p.Thr234Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs587783005, ExAC 0.02%). This variant has been observed to be homozygous or in combination with another BTD variant in individuals affected with biotinidase deficiency (PMID: 24797656, 27657684) and in one of those individuals it has been observed on the opposite chromosome (in trans) from another pathogenic variant. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 156003). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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