Submissions for variant NM_001370658.1(BTD):c.1301A>G (p.Tyr434Cys)

gnomAD frequency: 0.00004  dbSNP: rs397514345

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524591	SCV000630327	pathogenic	Biotinidase deficiency	2023-11-25	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 454 of the BTD protein (p.Tyr454Cys). This variant is present in population databases (rs397514345, gnomAD 0.2%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 26810761, 29995633; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 458806). 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.
Counsyl	RCV000524591	SCV000796970	uncertain significance	Biotinidase deficiency	2018-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001578266	SCV001805821	uncertain significance	not provided	2021-08-12	criteria provided, single submitter	clinical testing	Reported in one individual with profound biotinidase deficiency in whom two known pathogenic variants in the BTD gene were also found. In this individual, the Y454C variant was in cis with one of the known pathogenic variants with the other pathogenic variant on the opposite allele (Wolf et al., 2005); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 30616616, 26810761, 15776412, 31973013)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001578266	SCV002047169	likely pathogenic	not provided	2021-05-28	criteria provided, single submitter	clinical testing	The variant has been reported in multiple individuals with profound or partial biotinidase deficiency (PMID: 33312878 (2020), 29995633 (2018), 26810761 (2016), 15776412 (2005)). Variant occurs in 3 or more cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and at least 3 cases have phenotype known to be consistent with disease. Variant is predicted to have a damaging effect on the protein.Based on the available information, the variant is predicted to be likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282207	SCV002572127	uncertain significance	not specified	2024-03-29	criteria provided, single submitter	clinical testing	Variant summary: BTD c.1301A>G (p.Tyr434Cys) 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 0.00026 in 251422 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BTD causing Biotinidase Deficiency (0.00026 vs 0.0046), allowing no conclusion about variant significance. c.1301A>G has been reported in the literature in newborns with features of biotinidase deficiency to include cases where it was reported in cis with another presumably pathogenic variant (example, Akgun_2021, Seker-Yilmaz_2018, Ercan_2020, Procter_2016, Wolf_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in a homozygous genotype (Ercan_2020). The most pronounced variant effect results in 26%-36% of normal activity depending upon the methodology used. The following publications have been ascertained in the context of this evaluation (PMID: 26810761, 29353266, 33189081, 34448386, 15776412). ClinVar contains an entry for this variant (Variation ID: 458806). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Revvity Omics, Revvity	RCV000524591	SCV003822366	likely pathogenic	Biotinidase deficiency	2022-07-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000524591	SCV004211424	likely pathogenic	Biotinidase deficiency	2024-03-16	criteria provided, single submitter	clinical testing