Submissions for variant NM_001370658.1(BTD):c.1395C>G (p.His465Gln)

gnomAD frequency: 0.00009  dbSNP: rs201604102

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022015	SCV000832890	pathogenic	Biotinidase deficiency	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 485 of the BTD protein (p.His485Gln). This variant is present in population databases (rs201604102, gnomAD 0.02%). This missense change has been observed in individual(s) with profound biotinidase deficiency (PMID: 25967232, 26810761, 30912303; internal data). 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: 25090). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BTD protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000022015	SCV001136349	pathogenic	Biotinidase deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002477005	SCV002774329	pathogenic	not provided	2021-08-13	criteria provided, single submitter	clinical testing	The variant has been reported in individuals with reduced biotinidase activity in the published literature, including in a homozygous child with profound biotinidase deficiency (PMID: 25967232 (2015), 26810761 (2016), 30912303 (2019), 31801038 (2020)). Therefore, the variant is classified as pathogenic.
Ambry Genetics	RCV002513165	SCV003589835	likely pathogenic	Inborn genetic diseases	2022-01-31	criteria provided, single submitter	clinical testing	The c.1455C>G (p.H485Q) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a C to G substitution at nucleotide position 1455, causing the histidine (H) at amino acid position 485 to be replaced by a glutamine (Q). Based on data from gnomAD, the G allele has an overall frequency of <0.01% (5/282840) total alleles studied. The highest observed frequency was 0.02% (5/24966) of African alleles. This alteration has been detected as homozygous and as compound heterozygous with another BTD pathogenic mutation in individuals with profound biotinidase deficiency (Lara, 2015; Procter, 2016). This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in some other vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV000022015	SCV004211452	likely pathogenic	Biotinidase deficiency	2024-02-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000022015	SCV005660302	likely pathogenic	Biotinidase deficiency	2024-02-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000022015	SCV000800642	uncertain significance	Biotinidase deficiency	2017-12-28	flagged submission	clinical testing
Natera, Inc.	RCV000022015	SCV001461227	likely pathogenic	Biotinidase deficiency	2020-09-16	no assertion criteria provided	clinical testing