ClinVar Genomic variation as it relates to human health

The BTD c.1595C>T; p.Thr532Met variant (rs104893688), is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with partial to profound biotinidase deficiency (Cowan 2012, Funghini 2002, Laszlo 2003, Norrgard 1999, Ohlsson 2010, Pomponio 2000, Swango 1998, Wiltink 2016, Wolf 2017). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 1897), and is found in the non-Finnish European population with an allele frequency of 0.015% (19/125,971 alleles) in the Genome Aggregation Database. The threonine at codon 532 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Thr532Met variant is considered to be severely 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. Funghini S et al. Two new mutations in children affected by partial biotinidase deficiency ascertained by newborn screening. J Inherit Metab Dis. 2002 Aug;25(4):328-30. Laszlo A et al. Neonatal screening for biotinidase deficiency in Hungary: clinical, biochemical and molecular studies. J Inherit Metab Dis. 2003;26(7):693-8. Norrgard KJ 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 Jul;46(1):20-7. Ohlsson A et al. Profound biotinidase deficiency: a rare disease among native Swedes. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S175-8. Pomponio RJ et al. Novel mutations cause biotinidase deficiency in Turkish children. J Inherit Metab Dis. 2000 Mar;23(2):120-8. Swango KL et al. Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. Hum Genet. 1998 May;102(5):571-5. Wiltink RC et al. Neonatal screening for profound biotinidase deficiency in the Netherlands: consequences and considerations. Eur J Hum Genet. 2016 Oct;24(10):1424-9. Wolf B. Successful outcomes of older adolescents and adults with profound biotinidase deficiency identified by newborn screening. Genet Med. 2017 Apr;19(4):396-402.

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS4,PM1,PM2,PM3,PP3.

Variant summary: BTD c.1535C>T (p.Thr512Met, also known as c.1595C>T/p.Thr532Met in NM_000060) results in a non-conservative amino acid change located in the Vanin, C-terminal domain (IPR043957) of 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 6.9e-05 in 245398 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BTD causing Biotinidase Deficiency (6.9e-05 vs 0.0046), allowing no conclusion about variant significance. This variant has been reported in the literature in multiple individuals (both homozygous and compound heterozygous state) affected with partial to profound Biotinidase Deficiency (example: Pomponio_2000, Lara_2015). These data indicate that the variant is very likely to be associated with disease. Less than 10% of mean normal enzymatic activity was seen in serum or plasma of patients who were homozygous for the variant of interest (Pomponio_2000). Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The variant found in at least one symptomatic patient. 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.

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 532 of the BTD protein (p.Thr532Met). This variant is present in population databases (rs104893688, gnomAD 0.02%). This missense change has been observed in individual(s) with biotinidase deficiency (PMID: 9654207, 10400129, 10801053, 21752405, 22011816, 22698809, 27657684). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Mediterranean ancestry (PMID: 9654207, 10400129, 10801053, 21752405, 22011816, 22698809, 27657684). ClinVar contains an entry for this variant (Variation ID: 1897). 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.

BTD: PM3:Very Strong, PM2, PS3:Supporting

The c.1595C>T (p.T532M) alteration is located in exon 4 (coding exon 4) of the BTD gene. This alteration results from a C to T substitution at nucleotide position 1595, causing the threonine (T) at amino acid position 532 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.008% (22/276796) total alleles studied. The highest observed frequency was 0.015% (19/125972) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in conjunction with other BTD variants in many individuals with features consistent with biotinidase deficiency; in at least one instance, the variants were identified in trans (Forny, 2022; Funghini, 2020; Wolf, 2017; Wiltink, 2016; Lara, 2015; Ohlsson, 2010; Pomponio, 2000; Norrgard, 1999; Swango, 1998). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as p.(T532M); This variant is associated with the following publications: (PMID: 26361991, 26810761, 27657684, 26589311, 25754625, 14707518, 25174816, 12227467, 22698809, 9654207, 10801053, 30912303, 34426522, 35805799, 10400129)

The BTD c.1595C>T variant is predicted to result in the amino acid substitution p.Thr532Met. This variant, also known as c.1535C>T (p.Thr512Met) in an alternate transcript (NM_001370658.1), has been reported in the homozygous and compound heterozygous state in individuals with biotinidase deficiency (Norrgard. 1999. PubMed ID: 10400129; László et al. 2003. PubMed ID: 14707518; Wolf et al. 2005. PubMed ID: 15776412; Wolf. 2017. PubMed ID: 27657684; Carvalho. 2019. PubMed ID: 30912303). This variant has been interpreted as pathogenic by multiple labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/1897/). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.