ClinVar Genomic variation as it relates to human health

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)

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; 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.

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.

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.