ClinVar Genomic variation as it relates to human health

The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have phenotype known to be consistent with disease. The variant predicted to have a damaging effect on the protein and is damaging to protein function(s) relevant to disease mechanism.

Variant summary: BTD c.1207T>C (p.Cys403Arg) 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 was absent in 251372 control chromosomes. c.1207T>C, described as p.Cys423Arg, has been reported at a compound heterozygous state along with different apparently pathogenic variants in at-least four individuals affected with Biotinidase Deficiency (examples, Forny_2022, Iseghem_2019, Pomponio_1997, Wolf_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35195902, 31035122, 9396567, 27657684). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (PATH, n=1, Likely pathogenic, n=2, VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

This variant is present in population databases (rs397514412, gnomAD 0.007%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 423 of the BTD protein (p.Cys423Arg). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 9396567, 27657684, 31035122). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 25073). 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. For these reasons, this variant has been classified as Pathogenic.

NM_000060.2(BTD):c.1267T>C(C423R) is a missense variant classified as a variant of uncertain significance in the context of biotinidase deficiency. C423R has been observed in cases with relevant disease (PMID: 10400129, 9396567, 31035122). Functional assessments of this variant are not available in the literature. C423R has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, there is insufficient evidence to classify NM_000060.2(BTD):c.1267T>C(C423R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.