ClinVar Genomic variation as it relates to human health

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.

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.

Variant summary: BTD c.1301A>G (p.Tyr434Cys) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. 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 observed in multiple individuals affected with Biotinidase Deficiency (Ercan_2020, Canda_2018, Sharma_2023, Internal data). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 26%-35% of normal activity (Ercan_2020). The following publications have been ascertained in the context of this evaluation (PMID: 34448386, 33189081, 26810761, 29353266, 15776412, 29995633, 31973013, 38299772). ClinVar contains an entry for this variant (Variation ID: 458806). Based on the evidence outlined above, the variant was classified as pathogenic.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(Y454C); This variant is associated with the following publications: (PMID: 30616616, 33312878, 15776412, 29995633, 26810761, 31973013, 34271776, 29353266)

PM2_supporting, PP3_supporting, PM3_moderate, PP4_strong

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.

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].

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.