Submissions for variant NM_001370658.1(BTD):c.1372G>A (p.Ala458Thr)

gnomAD frequency: 0.00014  dbSNP: rs181396238

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000022034	SCV000800692	uncertain significance	Biotinidase deficiency	2018-04-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022034	SCV000963906	pathogenic	Biotinidase deficiency	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 478 of the BTD protein (p.Ala478Thr). This variant is present in population databases (rs181396238, gnomAD 0.01%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 26810761). ClinVar contains an entry for this variant (Variation ID: 25108). 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 expected to disrupt BTD protein function with a positive predictive value of 95%. This variant disrupts the p.Ala478 amino acid residue in BTD. Other variant(s) that disrupt this residue have been observed in individuals with BTD-related conditions (PMID: 19757147), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266891	SCV001445071	uncertain significance	Inborn genetic diseases	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271373	SCV002556111	uncertain significance	not specified	2022-06-02	criteria provided, single submitter	clinical testing	Variant summary: BTD c.1372G>A (p.Ala458Thr) results in a non-conservative amino acid change in the last exon of 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 8e-06 in 251444 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1372G>A has been reported in a compound heterozygous individual affected with Biotinidase Deficiency (Procter_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000022034	SCV004211395	likely pathogenic	Biotinidase deficiency	2024-03-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003476902	SCV004220739	likely pathogenic	not provided	2023-04-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/251444 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with biotinidase deficiency (PMID: 2681076 (2016)). Functional analysis demonstrated this variant to cause a low BTD serum level compared to a matched control (PMID: 2681076 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
Natera, Inc.	RCV000022034	SCV001461226	uncertain significance	Biotinidase deficiency	2020-09-16	no assertion criteria provided	clinical testing