Submissions for variant NM_001370658.1(BTD):c.1211G>A (p.Cys404Tyr)

dbSNP: rs397514335

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493447	SCV000582965	likely pathogenic	not provided	2015-12-07	criteria provided, single submitter	clinical testing	The C424Y variant has been reported previously in a patient with profound biotinidase deficiency who was homozygous for the C424Y variant (Wolf et al. 2005). The C424Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. C424Y 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Position 424 is reported to be crucial for ester formation and binding of the biotinyl-moiety in the active site of the biotinidase enzyme (Wolf et al., 2005). A missense variant at the same residue (C424S) and in nearby residues (C418S, C423R, C423S) have also been reported in the Human Gene Mutation Database in association with biotinidase deficiency (Stenson et al., 2014). Therefore, we interpret the C424Y variant to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000022000	SCV001407360	pathogenic	Biotinidase deficiency	2021-08-07	criteria provided, single submitter	clinical testing	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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys424 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15776412, 29359854). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been observed to be homozygous in an individual affected with biotinidase deficiency (PMID: 15776412). ClinVar contains an entry for this variant (Variation ID: 25075). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 424 of the BTD protein (p.Cys424Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000022000	SCV003800888	likely pathogenic	Biotinidase deficiency	2023-01-06	criteria provided, single submitter	clinical testing	Variant summary: BTD c.1211G>A (p.Cys404Tyr) 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 allele was found at a frequency of 4e-06 in 251376 control chromosomes (gnomAD). c.1211G>A has been reported in the literature in at least one homozygous individual affected with profound Biotinidase Deficiency (Wolf_2005). These data indicate that the variant may be associated with disease. Serum biotinidase activity was completely absent (0% of control) in this homozygous individual (Wolf_2005). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.