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

dbSNP: rs587783005

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000144060	SCV000915027	likely pathogenic	Biotinidase deficiency	2017-10-09	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000144060	SCV000933006	pathogenic	Biotinidase deficiency	2023-09-09	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 234 of the BTD protein (p.Thr234Ile). This variant is present in population databases (rs587783005, gnomAD 0.03%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 24797656, 27657684). 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: 156003). 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. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000144060	SCV002073122	likely pathogenic	Biotinidase deficiency		criteria provided, single submitter	clinical testing	The missense variant p.T214I in BTD (NM_001281723.3) has been reported previously in homozygous and compound heterozygous state in affected individuals (Li H et al,Wolf B et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic. Functional data is not available for this variant. The p.T214I variant is observed in 8/30,616 (0.0261%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between threonine and isoleucine. The p.T214I missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 214 of BTD is conserved in all mammalian species. The nucleotide c.641 in BTD is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000144060	SCV002802574	likely pathogenic	Biotinidase deficiency	2021-11-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000144060	SCV002819739	pathogenic	Biotinidase deficiency	2022-12-22	criteria provided, single submitter	clinical testing	Variant summary: BTD c.641C>T (p.Thr214Ile), also known as c.701C>T (p.Thr234Ile), results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251482 control chromosomes. c.641C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Biotinidase Deficiency (Li_2014, Wolf_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000144060	SCV004211441	pathogenic	Biotinidase deficiency	2024-01-05	criteria provided, single submitter	clinical testing
Molecular Genetics Diagnostic Laboratory, Detroit Medical Center University Laboratories	RCV000144060	SCV000189133	pathogenic	Biotinidase deficiency		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000144060	SCV002081561	pathogenic	Biotinidase deficiency	2017-06-15	no assertion criteria provided	clinical testing