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

gnomAD frequency: 0.00004  dbSNP: rs397514345

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524591	SCV000630327	pathogenic	Biotinidase deficiency	2024-12-31	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; internal data). 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). 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.
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
Neuberg Centre For Genomic Medicine, NCGM	RCV000524591	SCV005374757	uncertain significance	Biotinidase deficiency		criteria provided, single submitter	clinical testing	The observed missense c.1301A>G(p.Tyr434Cys) variant in BTD gene has been reported previously in compound heterozygous state in multiple individuals affected with biotinidase deficiency (Al-Eitan LN, et al., 2020; Muthaffar OY., 2021; Baykal T, et al., 2005). This variant has also been observed to segregate with disease in related individuals. The p.Tyr434Cys variant has been reported with allele frequency of 0.03% in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic / Likely Pathogenic. Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Tyr at position 434 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. Another significant variant [c.1270G>C | p.Asp424His] in BTD gene was detected in the spouse (EX-2323A), id: 30607800132].
Fulgent Genetics, Fulgent Genetics	RCV000524591	SCV005660300	likely pathogenic	Biotinidase deficiency	2024-05-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751584	SCV005355307	likely pathogenic	BTD-related disorder	2024-05-13	no assertion criteria provided	clinical testing	The BTD c.1361A>G variant is predicted to result in the amino acid substitution p.Tyr454Cys. This variant has been reported along with an additional BTD variant(s) in multiple patients with profound biotinidase deficiency (<10% enzyme activity) (Wolf et al. 2005. PubMed ID: 15776412; Procter et al. 2016. PubMed ID: 26810761; Canda et al. 2018. PubMed ID: 29995633). It has also been reported in patients with partial biotinidase deficiency (10%-30% enzyme activity) (Hsu et al. 2019. PubMed ID: 30616616; Funghini et al. 2020. PubMed ID: 33312878) and in several patients with abnormal newborn screen results suggestive of biotinidase deficiency (Seker Yilmaz et al. 2018. PubMed ID: 29353266). This variant is reported in 0.21% of alleles in individuals of South Asian descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic.