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

gnomAD frequency: 0.00001  dbSNP: rs397514410

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021996	SCV001575614	likely pathogenic	Biotinidase deficiency	2020-01-30	criteria provided, single submitter	clinical testing	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 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with biotinidase deficiency (PMID: 14707518). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 25071). This variant is present in population databases (rs397514410, ExAC 0.006%). This sequence change replaces cysteine with serine at codon 418 of the BTD protein (p.Cys418Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine.
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
Natera, Inc.	RCV000021996	SCV002081575	likely pathogenic	Biotinidase deficiency	2021-07-02	no assertion criteria provided	clinical testing