NM_001370658.1(BTD):c.1552C>T (p.Arg518Cys) AND Biotinidase deficiency

Clinical significance:Pathogenic (Last evaluated: Dec 19, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
8 submissions [Details]
Record status:
current
Accession:
RCV000001975.13

Allele description [Variation Report for NM_001370658.1(BTD):c.1552C>T (p.Arg518Cys)]

NM_001370658.1(BTD):c.1552C>T (p.Arg518Cys)

Gene:
BTD:biotinidase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.1
Genomic location:
Preferred name:
NM_001370658.1(BTD):c.1552C>T (p.Arg518Cys)
Other names:
R538C
HGVS:
  • NC_000003.12:g.15645468C>T
  • NG_008019.1:g.48721C>T
  • NG_008019.2:g.49117C>T
  • NM_000060.4:c.1612C>T
  • NM_001281723.3:c.1552C>T
  • NM_001281724.3:c.1552C>T
  • NM_001281725.2:c.1552C>T
  • NM_001323582.1:c.1552C>T
  • NM_001370658.1:c.1552C>TMANE SELECT
  • NM_001370752.1:c.1015+537C>T
  • NM_001370753.1:c.399+3411C>T
  • NP_000051.1:p.Arg538Cys
  • NP_001268652.2:p.Arg518Cys
  • NP_001268653.2:p.Arg518Cys
  • NP_001268654.1:p.Arg518Cys
  • NP_001310511.1:p.Arg518Cys
  • NP_001357587.1:p.Arg518Cys
  • NC_000003.11:g.15686975C>T
  • P43251:p.Arg538Cys
  • c.1612C>T
Protein change:
R518C; ARG538CYS
Links:
UniProtKB: P43251#VAR_005121; OMIM: 609019.0003; dbSNP: rs80338686
NCBI 1000 Genomes Browser:
rs80338686
Molecular consequence:
  • NM_001370752.1:c.1015+537C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001370753.1:c.399+3411C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001281723.3:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281724.3:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281725.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001323582.1:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370658.1:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV000022133OMIMno assertion criteria providedPathogenic
(Apr 1, 1997)
germlineliterature only

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

SCV000040404GeneReviewsno assertion criteria providedpathologic
(Mar 15, 2011)
not providedcuration

SCV000042698Research and Development, ARUP Laboratoriesno assertion criteria providedPathogenic
(Feb 17, 2017)
germlineliterature only

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

SCV000711423Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Sep 2, 2016)
germlineclinical testing

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

SCV000754947Invitaecriteria provided, single submitter
Pathogenic
(Apr 2, 2018)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000894302Fulgent Genetics,Fulgent Geneticscriteria provided, single submitter
Pathogenic
(Oct 31, 2018)
unknownclinical testing

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

SCV001194032Myriad Women's Health, Inc.criteria provided, single submitter
Pathogenic
(Dec 19, 2019)
unknownclinical testing

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

Citation Link,

SCV001461230Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedliterature only
not providedgermlinenot provided21not providednot providednot providedliterature only, clinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot providednot providednot providedcuration
not providedunknownunknownnot providednot providednot providednot providednot providedclinical 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 systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020
See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000022133.3

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

Description

In 10 of 30 symptomatic children with profound biotinidase deficiency (253260), Pomponio et al. (1997) identified a 1612C-T transition in a CpG dinucleotide in exon D of the BTD gene, resulting in an arg538-to-cys (R538C) substitution. Five of the patients were compound heterozygous for this mutation and a deletion/insertion mutation (609019.0001). There was no detectable biotinidase protein in sera of homozygous children, and the authors suggested that the R538C mutation results in abnormal disulfide bond formation, rapid degradation of the aberrant enzyme, and failure to secrete the mutant enzyme from the cells into the blood. Pomponio et al. (1997) reported that the R538C mutation is the second most common mutation causing biotinidase deficiency.

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

From GeneReviews, SCV000040404.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Research and Development, ARUP Laboratories, SCV000042698.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000711423.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (2)

Description

The p.Arg538Cys variant in BTD has been previously identified in at least 5 comp ound heterozygous and 2 homozygous individuals with severe biotinidase deficienc y and it is the second most common mutation in the biotinidase gene that causes profound biotinidase deficiency in symptomatic children. All these patients had no biotinyl transferase activity in their serum and <10% of mean normal biotiny l-hydrolase activity (Pomponio 1997). This variant has also been identified in 8 /114,620 of chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs80338686); however, this frequency is low enough to b e consistent with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for biotinidase deficiency in an autoso mal recessive manner based upon case and allelic observations and functional evi dence.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided2not provided1not provided

From Invitae, SCV000754947.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces arginine with cysteine at codon 538 of the BTD protein (p.Arg538Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs80338686, ExAC 0.02%). This variant has been reported as homozygous or in combination with another BTD variant in several individuals affected with biotinidase deficiency (PMID: 9099842, 27657684, 27207447). ClinVar contains an entry for this variant (Variation ID: 1898). 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. A different missense substitution at this codon (p.Arg538Ser) has been determined to be pathogenic (PMID: 22698809, Invitae). This suggests that the arginine residue is critical for BTD protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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

From Fulgent Genetics,Fulgent Genetics, SCV000894302.1

#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 Myriad Women's Health, Inc., SCV001194032.2

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

Description

NM_000060.2(BTD):c.1612C>T(R538C) is classified as pathogenic in the context of biotinidase deficiency. Sources cited for classification include the following: PMID 9099842 and 17185019. Classification of NM_000060.2(BTD):c.1612C>T(R538C) 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.

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

From Natera, Inc., SCV001461230.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2021

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