Submissions for variant NM_001370658.1(BTD):c.364C>A (p.Pro122Thr)

dbSNP: rs397514357

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000438885	SCV000521148	likely pathogenic	not provided	2016-11-10	criteria provided, single submitter	clinical testing	The P142T pathogenic variant in the BTD gene has been reported previously in the compound heterozygous and homozygous states in individuals with biotinidase deficiency (Sarafoglou et al., 2009; Gannavarapu et al., 2015). The P142T variant is not observed in large population cohorts (Lek et al., 2016; Exome Variant Server). The P142T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The P142T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000021923	SCV000996436	likely pathogenic	Biotinidase deficiency	2019-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266904	SCV001445084	uncertain significance	Inborn genetic diseases	2019-03-20	criteria provided, single submitter	clinical testing	The alteration results in an amino acid change:_x000D_ _x000D_ The c.424C>A (p.P142T) alteration is located in coding exon 3 of the BTD gene. This alteration results from a C to A substitution at nucleotide position 424, causing the proline (P) at amino acid position 142 to be replaced by a threonine (T). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the BTD c.424C>A alteration was not observed with coverage at this location. The amino acid change has been observed in affected individuals: _x000D_ _x000D_ The p.P142T alteration has been reported heterozygous with a second alteration in the BTD gene and homozygous in patients with profound biotinidase deficiency. The majority of reported patients with this alteration to date are of Somali heritage (Sarafoglou, 2009; Gannavarapu, 2015). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.P142 amino acid is conserved in available vertebrate species. The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The p.P142T alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021923	SCV002228733	pathogenic	Biotinidase deficiency	2023-08-30	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 19757147, 26361991, 26589311). ClinVar contains an entry for this variant (Variation ID: 25004). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 142 of the BTD protein (p.Pro142Thr).
Counsyl	RCV000021923	SCV000796708	likely pathogenic	Biotinidase deficiency	2017-12-28	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904859	SCV004726478	pathogenic	BTD-related disorder	2023-11-02	no assertion criteria provided	clinical testing	The BTD c.424C>A variant is predicted to result in the amino acid substitution p.Pro142Thr. This variant is absent from a large population database (gnomad.broadinstitute.org), indicating it is rare. Furthermore, it has been reported in the homozygous or compound heterozygous state in several patients with profound biotinidase deficiency (Sarafoglou et al. 2009. PubMed ID: 19757147; Al-Jasmi et al. 2016. PubMed ID: 26589311; Gannavarapu et al. 2015. PubMed ID: 26361991; Tangeraas et al. 2020. PubMedID: 33123633). Taken together, we interpret this variant as pathogenic.