Submissions for variant NM_001370658.1(BTD):c.1246G>A (p.Glu416Lys)

gnomAD frequency: 0.00001  dbSNP: rs749460715

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483848	SCV000571983	likely pathogenic	not provided	2016-10-28	criteria provided, single submitter	clinical testing	The E436K 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. The E436K variant 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether the E436K variant is a pathogenic variant or a rare benign variant.
Myriad Genetics, Inc.	RCV000675109	SCV002060234	uncertain significance	Biotinidase deficiency	2021-11-08	criteria provided, single submitter	clinical testing	NM_000060.2(BTD):c.1306G>A(E436K) is a missense variant classified as a variant of uncertain significance in the context of biotinidase deficiency. E436K has been observed in cases with relevant disease (PMID: 30616616). Functional assessments of this variant are not available in the literature. E436K has been observed in population frequency databases (gnomAD: EAS 0.05%). In summary, there is insufficient evidence to classify NM_000060.2(BTD):c.1306G>A(E436K) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Invitae	RCV000675109	SCV002179420	likely pathogenic	Biotinidase deficiency	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 436 of the BTD protein (p.Glu436Lys). This variant is present in population databases (rs749460715, gnomAD 0.05%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 30616616; Invitae). 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: 422496). 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%. 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.