Submissions for variant NM_001370658.1(BTD):c.1193G>C (p.Cys398Ser)

gnomAD frequency: 0.00001  dbSNP: rs397514410

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021996	SCV001575614	pathogenic	Biotinidase deficiency	2024-02-29	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 418 of the BTD protein (p.Cys418Ser). This variant is present in population databases (rs397514410, gnomAD 0.003%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 14707518). 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: 25071). 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 with a positive predictive value of 95%. This variant disrupts the p.Cys418 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26810761, 27329734). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000021996	SCV004029303	pathogenic	Biotinidase deficiency	2023-07-28	criteria provided, single submitter	clinical testing	Variant summary: BTD c.1193G>C (p.Cys398Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR043957) 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 251336 control chromosomes (i.e., 2 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1193G>C has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Biotinidase Deficiency (BD), and many of these individuals had partial BD (e.g., Laszlo_2003, Milankovics_2007, SekerYilmaz_2018, Jezela-Stanek_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35627187, 14707518, 17185019, 29353266). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000021996	SCV004211449	likely pathogenic	Biotinidase deficiency	2023-12-07	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000021996	SCV005438453	pathogenic	Biotinidase deficiency	2024-12-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000021996	SCV002081575	likely pathogenic	Biotinidase deficiency	2021-07-02	no assertion criteria provided	clinical testing