NM_001370658.1(BTD):c.1192T>C (p.Cys398Arg) AND Biotinidase deficiency

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 25, 2024
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:: RCV000021994.13

Allele description [Variation Report for NM_001370658.1(BTD):c.1192T>C (p.Cys398Arg)]

NM_001370658.1(BTD):c.1192T>C (p.Cys398Arg)

Gene:

BTD:biotinidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.1

Genomic location:

Preferred name:

NM_001370658.1(BTD):c.1192T>C (p.Cys398Arg)

HGVS:

NC_000003.12:g.15645108T>C
NG_008019.2:g.48757T>C
NG_008019.3:g.48758T>C
NM_000060.4:c.1252T>C
NM_001281723.4:c.1192T>C
NM_001281724.3:c.1192T>C
NM_001281725.3:c.1192T>C
NM_001323582.2:c.1192T>C
NM_001370658.1:c.1192T>CMANE SELECT
NM_001370752.1:c.1015+177T>C
NM_001370753.1:c.399+3051T>C
NM_001407364.1:c.1192T>C
NM_001407365.1:c.1192T>C
NM_001407366.1:c.1192T>C
NM_001407367.1:c.1192T>C
NM_001407368.1:c.1192T>C
NM_001407369.1:c.1192T>C
NM_001407370.1:c.1192T>C
NM_001407371.1:c.1192T>C
NM_001407372.1:c.1192T>C
NM_001407373.1:c.1192T>C
NM_001407374.1:c.1192T>C
NM_001407375.1:c.1192T>C
NM_001407376.1:c.1192T>C
NM_001407377.1:c.1192T>C
NM_001407378.1:c.1192T>C
NP_000051.1:p.Cys418Arg
NP_001268652.2:p.Cys398Arg
NP_001268652.2:p.Cys398Arg
NP_001268653.2:p.Cys398Arg
NP_001268654.1:p.Cys398Arg
NP_001268654.1:p.Cys398Arg
NP_001310511.1:p.Cys398Arg
NP_001310511.1:p.Cys398Arg
NP_001357587.1:p.Cys398Arg
NP_001394293.1:p.Cys398Arg
NP_001394294.1:p.Cys398Arg
NP_001394295.1:p.Cys398Arg
NP_001394296.1:p.Cys398Arg
NP_001394297.1:p.Cys398Arg
NP_001394298.1:p.Cys398Arg
NP_001394299.1:p.Cys398Arg
NP_001394300.1:p.Cys398Arg
NP_001394301.1:p.Cys398Arg
NP_001394302.1:p.Cys398Arg
NP_001394303.1:p.Cys398Arg
NP_001394304.1:p.Cys398Arg
NP_001394305.1:p.Cys398Arg
NP_001394306.1:p.Cys398Arg
NP_001394307.1:p.Cys398Arg
NC_000003.11:g.15686615T>C
NM_001281723.3:c.1192T>C
NM_001281725.2:c.1192T>C
NM_001323582.1:c.1192T>C

Protein change:

C398R

Links:

dbSNP: rs397514408

NCBI 1000 Genomes Browser:

rs397514408

Molecular consequence:

NM_001370752.1:c.1015+177T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001370753.1:c.399+3051T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000060.4:c.1252T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281723.4:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281724.3:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001281725.3:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001323582.2:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001370658.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407364.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407365.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407366.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407367.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407368.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407369.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407370.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407371.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407372.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407373.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407374.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407375.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407376.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407377.1:c.1192T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407378.1:c.1192T>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000800681	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Mar 27, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27329734, 26810761 Citation Link,
SCV000938428	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26810761, 27329734, 14707518, 28492532
SCV004211445	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 25, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000800681

Counsyl

criteria provided, single submitter

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

Uncertain significance
(Mar 27, 2018)

unknown

clinical testing

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

Citation Link,

SCV000938428

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2023)

germline

clinical testing

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

SCV004211445

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 25, 2024)

unknown

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

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

Neonatal screening for profound biotinidase deficiency in the Netherlands: consequences and considerations.

Wiltink RC, Kruijshaar ME, van Minkelen R, Onkenhout W, Verheijen FW, Kemper EA, van Spronsen FJ, van der Ploeg AT, Niezen-Koning KE, Saris JJ, Williams M.

Eur J Hum Genet. 2016 Oct;24(10):1424-9. doi: 10.1038/ejhg.2016.65. Epub 2016 Jun 22.

PubMed [citation]

PMID:: 27329734
PMCID:: PMC5027693

See all PubMed Citations (5)

Details of each submission

From Counsyl, SCV000800681.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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, SCV000938428.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 418 of the BTD protein (p.Cys418Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 26810761, 27329734; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 25069). 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. This variant disrupts the p.Cys418 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 14707518), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	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

From Baylor Genetics, SCV004211445.2

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

#	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

Last Updated: Sep 29, 2024

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