ClinVar Genomic variation as it relates to human health

Variant summary: HLCS c.1522C>T (p.Arg508Trp) results in a non-conservative amino acid change located in the Biotinyl protein ligase (BPL) and lipoyl protein ligase (LPL), catalytic domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant is located at the third exonic nucleotide from a splice junction, suggesting it may impact normal splicing. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 246292 control chromosomes (gnomAD). The variant, c.1522C>T, has been reported in the literature in multiple homozygous individuals affected with Holocarboxylase Synthetase Deficiency (Malvagia_2005, Tang_2003, Hui_2011). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with holocarboxylase synthetase deficiency, (MIM#253270). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (7 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated active site within the BPL domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and in multiple homozygous and compound heterozygous patients with late onset holocarboxylase synthetase deficiency (ClinVar, PMID: 12633764, PMID: 21874615, PMID: 32358368). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies on transfected cells have shown this mutant protein has impaired interaction with Syn67 (PMID: 20026029). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 508 of the HLCS protein (p.Arg508Trp). This variant is present in population databases (rs119103229, gnomAD 0.02%). This missense change has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 8817339, 11185745, 16231399, 17407983, 21874615). 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: 1909). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HLCS function (PMID: 10068510, 20026029). For these reasons, this variant has been classified as Pathogenic.

PS3+PM2_P+PM3_S+PP3