Submissions for variant NM_001370658.1(BTD):c.1137G>A (p.Met379Ile)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003499929	SCV004293423	pathogenic	Biotinidase deficiency	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 399 of the BTD protein (p.Met399Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 28971021). 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: 2734456). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BTD protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526995	SCV005040634	uncertain significance	not specified	2024-03-27	criteria provided, single submitter	clinical testing	Variant summary: BTD c.1137G>A (p.Met379Ile) results in a conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251400 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1137G>A has been reported in the literature in individuals affected with Biotinidase Deficiency (Porta_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28971021). ClinVar contains an entry for this variant (Variation ID: 2734456). Based on the evidence outlined above, the variant was classified as uncertain significance.