ClinVar Genomic variation as it relates to human health

A Heterozygous Missense variant c.535G>A in Exon 4 of the BTD gene that results in the amino acid substitution p.Val179Met was identified. This variant has been reported to ClinVar (25026 ) as Pathogenic and likely pathogenic with a status of (2 stars) criteria provided,multiple submitters, no conflicts The observed variant has amaximum allele frequency of 0.00002/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood thatthe variant is disease-causing. Experimental evidence suggests this variant results in abnormal protein function ( Borsatto T, et al., 2014). This variant has been observed in many individuals affected with Biotinidase deficiency reported by (Milánkovics I et al., 2007) Based on the above evidence this variant has been classified asPathogenic according to the ACMG guidelines.

The frequency of this variant in the general population, 0.000021 (6/282846 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant is associated with profound biotinidase deficiency although it has been reported in affected individuals with a second pathogenic variant and residual activity (PMID: 12359137 (2002), 25174816 (2014), 27329734 (2016)). Based on the available information, this variant is classified as pathogenic.

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 199 of the BTD protein (p.Val199Met). This variant is present in population databases (rs397514375, gnomAD 0.006%). This missense change has been observed in individual(s) with partial or profound biotinidase deficiency (PMID: 12359137, 15060693, 17185019, 25144890, 25174816, 28498829). ClinVar contains an entry for this variant (Variation ID: 25026). 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.535G>A (p.Val179Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251458 control chromosomes. c.535G>A has been reported in the literature as compound heterozygous genotypes in individuals affected with profound and partial Biotinidase Deficiency (example, Wolf_2002, Milankovis_2007, Neto_2004, Jay_2015, Borsatto_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25144890, 28498829, 12359137, 17185019, 15060693, 25174816)

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000025026). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

The BTD c.595G>A variant is predicted to result in the amino acid substitution p.Val199Met. This variant has been reported in the compound heterozygous or homozygous states in patients with biotinidase deficiency (Borsatto et al. 2014. PubMed ID: 25174816; Wolf et al. 2002. PubMed ID: 12359137; Wiltink et al. 2016. PubMed ID: 27329734; Jay et al. 2015. PubMed ID: 25144890; Milankovics et al. 2007. PubMed ID: 17185019; Neto et al. 2004. PubMed ID: 15060693; Canda et al. 2018. PubMed ID: 29995633). This variant was also described in the heterozygous state in individuals with aberrant newborn screening results (Thodi et al. 2011. PubMed ID: 22011816). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-15685958-G-A). In the ClinVar database, this variant has been listed as 'likely pathogenic' or 'pathogenic' by outside laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/25026/). This variant is interpreted as likely pathogenic.