ClinVar Genomic variation as it relates to human health

This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 510 of the ABCG5 protein (p.His510Asn). This variant is present in population databases (rs199984328, gnomAD 0.5%). This missense change has been observed in individual(s) with clinical features of sitosterolemia and/or familial hypercholesterolemia (PMID: 29353225, 30782472, 32041611). ClinVar contains an entry for this variant (Variation ID: 595462). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant disrupts the p.His510 amino acid residue in ABCG5. Other variant(s) that disrupt this residue have been observed in individuals with ABCG5-related conditions (PMID: 17228349), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The c.1528C>A variant in ABCG5 is observed in 169 alleles (~0.03% minor allele frequency with 0 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8), of which 139 alleles are observed in Asian populations with ~0.5% minor allele frequency. This variant has previously been reported in the literature in an individual of Asian ancestry with Sitosterolemia [PMID: 30782472] and in individuals with familial hypercholesterolemia [PMID: 29353225 – a study inAsian population; PMID: 32041611 – a Canadian study without ancestry information]; and it has also been deposited in ClinVar [ClinVar ID: 595462] as Variant of Uncertain Significance. The c.1528C>A variant is located in exon 11 of this 13-exon gene, and predicted to replace an evolutionarily conserved histidine amino acid with asparagine at position 510 (p.(His510Asn)) in the fourth of the six transmembrane domains of the encoded protein. In silico predictions are inconclusive of the p.(His510Asn) variant's effect (CADD v1.6 =25, REVEL = 0.377); however, there are no functional studies to support or refute these predictions. Based on available evidence this heterozygous c.1528 C>A p.(His510Asn) variant identified in ABCG5 is classified as a Variant of Uncertain Significance.

The p.H510N variant (also known as c.1528C>A), located in coding exon 11 of the ABCG5 gene, results from a C to A substitution at nucleotide position 1528. The histidine at codon 510 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported in a subject with features of sitosterolemia, who also had a splice site alteration in ABCG5 (Su X et al. J Clin Lipidol, 2019 Jan;13:246-250). This alteration has also been reported in subjects with features of hypercholesterolemia (Pek SLT et al. Atherosclerosis, 2018 02;269:106-116; Dron JS et al. BMC Med Genomics, 2020 02;13:23). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Variant summary: ABCG5 c.1528C>A (p.His510Asn) results in a conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 251376 control chromosomes, predominantly at a frequency of 0.0059 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCG5 causing Early Onset Coronary Artery Disease phenotype (0.005). c.1528C>A has been reported in the literature in individuals affected with Sitosterolemia and hypercholesterolemia (Pek_2018, Su_2019, Dron_2020), and a recent GWAS-like study using UK biobank rejected the association between this variant and Sitosterolemia with macrothrombocytopenia (Stefanucci_2023). These data do not allow any conclusion about variant significance. 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: 32041611, 29353225, 37647632, 30782472). ClinVar contains an entry for this variant (Variation ID: 595462). Based on the evidence outlined above, the variant was classified as likely benign.

Observed with a second ABCG5 variant in patients with sitosterolemia, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 35042526); 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: 29353225, 32041611, 32088153, 28971506, 35042526, 36981027, 30782472)

The ABCG5 c.1528C>A variant is predicted to result in the amino acid substitution p.His510Asn. This variant has been reported in one patient with familial hypercholesterolemia and in a compound heterozygous individual with sitosterolemia (Pek et al 2018. PubMed ID: 29353225; Su X et al 2019. PubMed ID: 30782472). This variant is reported in 0.58% of alleles in individuals of East Asian descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.