NM_001370658.1(BTD):c.683T>C (p.Ile228Thr) AND Biotinidase deficiency

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Pathogenic(2);Uncertain significance(1) (Last evaluated: Mar 5, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000021960.3

Allele description [Variation Report for NM_001370658.1(BTD):c.683T>C (p.Ile228Thr)]

NM_001370658.1(BTD):c.683T>C (p.Ile228Thr)

Gene:
BTD:biotinidase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.1
Genomic location:
Preferred name:
NM_001370658.1(BTD):c.683T>C (p.Ile228Thr)
HGVS:
  • NC_000003.12:g.15644599T>C
  • NG_008019.1:g.47852T>C
  • NG_008019.2:g.48248T>C
  • NM_001281723.3:c.683T>C
  • NM_001281724.3:c.683T>C
  • NM_001281725.2:c.683T>C
  • NM_001323582.1:c.683T>C
  • NM_001370658.1:c.683T>CMANE SELECT
  • NM_001370752.1:c.683T>C
  • NM_001370753.1:c.399+2542T>C
  • NP_001268652.2:p.Ile228Thr
  • NP_001268653.2:p.Ile228Thr
  • NP_001268654.1:p.Ile228Thr
  • NP_001310511.1:p.Ile228Thr
  • NP_001357587.1:p.Ile228Thr
  • NP_001357681.1:p.Ile228Thr
  • NC_000003.11:g.15686106T>C
  • NM_001281724.1:c.749T>C
Protein change:
I228T
Links:
dbSNP: rs397514382
NCBI 1000 Genomes Browser:
rs397514382
Molecular consequence:
  • NM_001370753.1:c.399+2542T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001281723.3:c.683T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281724.3:c.683T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281725.2:c.683T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001323582.1:c.683T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370658.1:c.683T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370752.1:c.683T>C - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000042629Research and Development, ARUP Laboratoriescriteria provided, single submitter
Pathogenic
(Feb 17, 2017)
germlineclinical testing

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

SCV000602896ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(May 23, 2019)
germlineclinical testing

Citation Link,

SCV000800591Counsylcriteria provided, single submitter
Uncertain significance
(Nov 14, 2017)
unknownclinical testing

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

Citation Link,

SCV001585143Invitaecriteria provided, single submitter
Pathogenic
(Mar 5, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Increased incidence of profound biotinidase deficiency among Hispanic newborns in California.

Cowan TM, Kazerouni NN, Dharajiya N, Lorey F, Roberson M, Hodgkinson C, Schrijver I.

Mol Genet Metab. 2012 Aug;106(4):485-7. doi: 10.1016/j.ymgme.2012.05.017. Epub 2012 May 30.

PubMed [citation]
PMID:
22698809

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 (3)

Details of each submission

From Research and Development, ARUP Laboratories, SCV000042629.2

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

Description

Enzyme activity @ < 0.4 U/L with a paired control in the normal range. Seen with c.528G>T,p.K176N.

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000602896.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The BTD c.743T>C; p.Ile248Thr variant (rs397514382) is reported in the literature in at least one individual affected with biotinidase deficiency who carried a second, pathogenic variant in BTD (Cowan 2012). This variant is reported in ClinVar (Variation ID: 25037), and is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 248 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Cowan TM et al. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Mol Genet Metab. 2012 Aug;106(4):485-7.

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

From Counsyl, SCV000800591.1

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

From Invitae, SCV001585143.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces isoleucine with threonine at codon 248 of the BTD protein (p.Ile248Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs397514382, ExAC 0.009%). This variant has been observed in combination with another BTD variant in an individual affected with biotinidase deficiency (PMID: 26810761). ClinVar contains an entry for this variant (Variation ID: 25037). 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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