Submissions for variant NM_001370658.1(BTD):c.697C>T (p.Pro233Ser)

gnomAD frequency: 0.00001  dbSNP: rs397514383

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000021961	SCV000800481	uncertain significance	Biotinidase deficiency	2017-01-24	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000021961	SCV002073119	likely pathogenic	Biotinidase deficiency		criteria provided, single submitter	clinical testing	The missense variant p.P233S in BTD (NM_001281723.3) has been reported before as P253S in a patient with biotinidase deficiency in a compund heterozygous state with another frameshift variant (Wolf B et al,2005). It has been submitted to ClinVar as Pathogenic/ Variants of uncertain significance. The p.P233S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.P233S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 233 of BTD is conserved in all mammalian species. The nucleotide c.697 in BTD is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Invitae	RCV000021961	SCV004292223	pathogenic	Biotinidase deficiency	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 253 of the BTD protein (p.Pro253Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 15776412). ClinVar contains an entry for this variant (Variation ID: 25039). 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.Pro253 amino acid residue in BTD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26810761). 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.
SingHealth Duke-NUS Institute of Precision Medicine	RCV000021961	SCV000853115	pathogenic	Biotinidase deficiency	2017-06-07	no assertion criteria provided	curation