Submissions for variant NM_001370658.1(BTD):c.419G>A (p.Cys140Tyr)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002664293	SCV003525117	likely pathogenic	Biotinidase deficiency	2023-03-10	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects BTD function (PMID: 31337602). This variant disrupts the p.Cys160 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 160 of the BTD protein (p.Cys160Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 25174816). ClinVar contains an entry for this variant (Variation ID: 2203313).
Baylor Genetics	RCV002664293	SCV004211483	likely pathogenic	Biotinidase deficiency	2022-09-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002664293	SCV005204091	likely pathogenic	Biotinidase deficiency	2024-06-21	criteria provided, single submitter	clinical testing	Variant summary: BTD c.419G>A (p.Cys140Tyr) 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 was absent in 251084 control chromosomes. c.419G>A has been reported in the literature in at-least one individual affected with Biotinidase Deficiency (Borsatto_2014). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence that variant reduced normal activity (Borsatto_2019). The following publications have been ascertained in the context of this evaluation (PMID: 25174816, 31337602).ClinVar contains an entry for this variant (Variation ID: 2203313). Based on the evidence outlined above, the variant was classified as likely pathogenic.