Submissions for variant NM_001370658.1(BTD):c.218A>G (p.Tyr73Cys)

dbSNP: rs397514348

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000021911	SCV000798916	likely pathogenic	Biotinidase deficiency	2018-03-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000021911	SCV001590142	pathogenic	Biotinidase deficiency	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 93 of the BTD protein (p.Tyr93Cys). This variant is present in population databases (rs397514348, gnomAD 0.003%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 12359137, 25144890, 26810761; Invitae). ClinVar contains an entry for this variant (Variation ID: 24993). 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%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000021911	SCV004099989	pathogenic	Biotinidase deficiency	2023-09-19	criteria provided, single submitter	clinical testing	Variant summary: BTD c.218A>G (p.Tyr73Cys) 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 251380 control chromosomes (gnomAD). c.218A>G (also known as c.278A>G/p.Y93C) has been reported in the literature in multiple individuals affected with Biotinidase Deficiency (examples: Wolf_2002, Jay_2016, Procter_2016, Maguolo_2021, Akgun_2021). 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: 34448386, 25144890, 34136440, 26810761, 12359137). Three submitters have cited 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	RCV000021911	SCV004211418	pathogenic	Biotinidase deficiency	2024-01-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV004584595	SCV005074653	pathogenic	not provided	2024-06-01	criteria provided, single submitter	clinical testing	BTD: PM3:Very Strong, PM2
Natera, Inc.	RCV000021911	SCV002081547	pathogenic	Biotinidase deficiency	2021-06-10	no assertion criteria provided	clinical testing