NM_001370658.1(BTD):c.908A>G (p.His303Arg) AND Biotinidase deficiency

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(2) (Last evaluated: Jun 24, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000021978.7

Allele description [Variation Report for NM_001370658.1(BTD):c.908A>G (p.His303Arg)]

NM_001370658.1(BTD):c.908A>G (p.His303Arg)

Gene:
BTD:biotinidase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.1
Genomic location:
Preferred name:
NM_001370658.1(BTD):c.908A>G (p.His303Arg)
Other names:
H323R
HGVS:
  • NC_000003.12:g.15644824A>G
  • NG_008019.1:g.48077A>G
  • NG_008019.2:g.48473A>G
  • NM_000060.4:c.968A>G
  • NM_001281723.3:c.908A>G
  • NM_001281724.3:c.908A>G
  • NM_001281725.2:c.908A>G
  • NM_001281726.2:c.*2686A>G
  • NM_001323582.1:c.908A>G
  • NM_001370658.1:c.908A>GMANE SELECT
  • NM_001370752.1:c.908A>G
  • NM_001370753.1:c.399+2767A>G
  • NP_000051.1:p.His323Arg
  • NP_001268652.2:p.His303Arg
  • NP_001268653.2:p.His303Arg
  • NP_001268654.1:p.His303Arg
  • NP_001310511.1:p.His303Arg
  • NP_001357587.1:p.His303Arg
  • NP_001357681.1:p.His303Arg
  • NC_000003.11:g.15686331A>G
  • NM_000060.2:c.968A>G
  • NM_000060.3:c.968A>G
  • NP_000051.1:p.His323Pro
  • P43251:p.His323Arg
  • c.968A>G
Protein change:
H303R
Links:
UniProtKB: P43251#VAR_005116; dbSNP: rs397507176
NCBI 1000 Genomes Browser:
rs397507176
Molecular consequence:
  • NM_001281726.2:c.*2686A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001370753.1:c.399+2767A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001281723.3:c.908A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281724.3:c.908A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281725.2:c.908A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001323582.1:c.908A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370658.1:c.908A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001370752.1:c.908A>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000042648Research and Development, ARUP Laboratoriesno assertion criteria providedPathogenic
(Feb 17, 2017)
germlineliterature only

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

SCV000630341Invitaecriteria provided, single submitter
Uncertain significance
(Feb 15, 2018)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001136346Mendelicscriteria provided, single submitter
Uncertain significance
(May 28, 2019)
unknownclinical testing

Citation Link,

SCV001454451Natera, Inc.no assertion criteria providedUncertain significance
(Sep 25, 2017)
germlineclinical testing

SCV001522810Baylor Geneticscriteria provided, single submitter
Pathogenic
(Jun 24, 2019)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, literature only
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Biotinidase deficiency: Spectrum of molecular, enzymatic and clinical information from newborn screening Ontario, Canada (2007-2014).

Gannavarapu S, Prasad C, DiRaimo J, Napier M, Goobie S, Potter M, Chakraborty P, Karaceper M, Munoz T, Schulze A, MacKenzie J, Li L, Geraghty MT, Al-Dirbashi OY, Rupar CA.

Mol Genet Metab. 2015 Nov;116(3):146-51. doi: 10.1016/j.ymgme.2015.08.010. Epub 2015 Aug 31.

PubMed [citation]
PMID:
26361991

Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene.

Swango KL, Demirkol M, Hüner G, Pronicka E, Sykut-Cegielska J, Schulze A, Mayatepek E, Wolf B.

Hum Genet. 1998 May;102(5):571-5. Erratum in: Hum Genet 1998 Jun;102(6):712.

PubMed [citation]
PMID:
9654207
See all PubMed Citations (5)

Details of each submission

From Research and Development, ARUP Laboratories, SCV000042648.2

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

From Invitae, SCV000630341.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces histidine with arginine at codon 323 of the BTD protein (p.His323Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs397507176, ExAC 1.6%). This variant has been reported in the literature in two individuals affected with partial BTD deficiency who showed 10-30% of normal BTD enzymatic activity (PMID: 9654207, 26361991), in combination with a BTD pathogenic variant in an individual with normal enzymatic activity (PMID: 26361991), and in one individual newborn screening positive for BTD deficiency but with normal enzymatic activity after confirmatory analyses (PMID: 27329734). ClinVar contains an entry for this variant (Variation ID: 38278). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change that has been reported in individuals with partial BTD deficiency as well as in individuals with normal enzymatic activity. Further genetic and/or functional data are needed to classify this variant conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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

From Mendelics, SCV001136346.1

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

From Natera, Inc., SCV001454451.1

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

From Baylor Genetics, SCV001522810.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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

Last Updated: Oct 7, 2021

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