ClinVar Genomic variation as it relates to human health

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11668630, 17382128, 26334177, 22698809, 10400129, 26810761)

The c.528G>T (p.Lys176Asn) BTD pathogenic variant (also known as K176N) has been reported in multiple individuals with biotinidase deficiency (PMID: 26810761 (2016), 22698809 (2012), 1668630 (1991)). Individuals who are homozygous for the c.528G>T (p.Lys176Asn) BTD pathogenic variant have been described as having profound biotinidase deficiency with low biotinyl hydrolase activity, low biotinyl transferase activity, and low serum levels of cross reacting material to antibody prepared against purified human serum biotinidase (PMID: 10400129 (1999)).

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 176 of the BTD protein (p.Lys176Asn). This variant is present in population databases (rs397514367, gnomAD 0.08%). This missense change has been observed in individual(s) with profound biotinidase deficiency (<10% normal activity) (PMID: 10400129, 22698809). ClinVar contains an entry for this variant (Variation ID: 25018). 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.

The c.468G>T; p.Lys156Asn variant (rs397514367) is reported in the literature in the homozygous or compound heterozygous state in multiple Hispanic individuals affected with biotinidase deficiency (Cowan 2012, Norrgard 1999, Procter 2016). This variant is reported in ClinVar (Variation ID: 25018) and is found in the Latino population with an allele frequency of 0.074% (26/35434 alleles) in the Genome Aggregation Database. The lysine at codon 176 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.633). Based on available information, this variant is considered to be pathogenic. References: Cowan TM et al. Increased incidence of profound biotinidase deficiency among Hispanic newborns in California. Mol Genet Metab. 2012 Aug;106(4):485-7. PMID: 22698809 Norrgard K et al. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res 1999 46(1):20-7. PMID: 10400129 Procter M et al. Forty-eight novel mutations causing biotinidase deficiency. Mol Genet Metab. 2016 Mar;117(3):369-72. PMID: 26810761

Variant summary: BTD c.468G>T (p.Lys156Asn) 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 9.5e-05 in 251394 control chromosomes, predominantly at a frequency of 0.00069 within the Latino subpopulation in the gnomAD database. This frequency is not higher than predicted for a pathogenic variant in BTD causing Biotinidase Deficiency (9.5e-05 vs 0.0046). c.468G>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Biotinidase Deficiency (example: Cowan_2012). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic