ClinVar Genomic variation as it relates to human health

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 574 of the ABCG8 protein (p.Gly574Arg). This variant is present in population databases (rs137852988, gnomAD 0.01%). This missense change has been observed in individual(s) with sitosterolemia (PMID: 11099417, 12124998, 15996216, 25073796, 32088153, 34969652). 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: 4968). 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 ABCG8 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCG8 function (PMID: 15054092). This variant disrupts the p.Gly574 amino acid residue in ABCG8. Other variant(s) that disrupt this residue have been observed in individuals with ABCG8-related conditions (PMID: 11452359), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

This variant is interpreted as a Likely Pathogenic, for Sitosterolemia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:15054092).

The ABCG8 c.1720G>A (p.Gly574Arg) variant has been found in a homozygous state in at least six individuals with sitosterolemia, five of whom are from the Amish population (Berge et al. 2000; Lee et al. 2001; Solca et al. 2005; Horenstein et al. 2013; Ruiz et al. 2015). Horenstein et al. (2013) determined that the carrier frequency for the p.Gly574Arg variant was 0.76% in the healthy Amish population and identified a statistically significant increase in plant sterol plasma levels in carriers compared to non-carriers. Control data are unavailable for this variant, which is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Gly574Arg variant is classified as likely pathogenic for sitosterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This variant has been previously reported as a compound heterozygous change with a nonsense variant in one individual with Sitosterolemia and as homozygous change in several individuals with Sitosterolemia (PMID: 11264985, 12124998, 25073796, 15996216). Functional studies have shown that this variant is associated decreased protein maturation (PMID: 15054092). The c.1720G>A (p.Gly574Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.006% (18/282058) and thus is presumed to be rare. The allele frequency in the Amish population is 1.5% (15/984), suggesting a founder effect (PMID: 23241408). The c.1720G>A (p.Gly574Arg) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a discordant effect on protein function. Based on the available evidence, the c.1720G>A (p.Gly574Arg) variant is classified as Pathogenic.

The missense variant p.G574R in ABCG8 (NM_022437.3) has been reported as a common variant in the Amish population (Horenstein RB et al,2013; Ruiz XD et al). The variant has been submitted to ClinVar as Pathogenic.The p.G574R variant is observed in 11/1,13,234 (0.0097%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G574R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1720 in ABCG8 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. The variant has been detected in a heterozygous state in her parents.

The p.G574R pathogenic mutation (also known as c.1720G>A), located in coding exon 11 of the ABCG8 gene, results from a G to A substitution at nucleotide position 1720. The glycine at codon 574 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been reported in several homozygous sitosterolemia cases and has been described as an Amish founder mutation (Kwiterovich PO et al. Lancet, 1981 Feb;1:466-9; Berge KE et al. Science, 2000 Dec;290:1771-5; Heimerl S et al. Hum. Mutat., 2002 Aug;20:151; Solcà C et al. Clin. Genet., 2005 Aug;68:174-8; Horenstein RB et al, 2013 Feb;33:413-9). One in vitro study indicates that this alteration may impact protein function (Graf GA et al. J. Biol. Chem., 2004 Jun;279:24881-8). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Thonghin N et al, 2018 12;18:17). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

The ABCG8 c.1720G>A variant is predicted to result in the amino acid substitution p.Gly574Arg. This variant has been reported in patients with autosomal recessive sitosterolemia and is a frequent variant among the Amish population (Berge et al. 2000. PubMed ID: 11099417; Heimerl et al. 2002. PubMed ID: 12124998; Horenstein et al. 2013. PubMed ID: 23241408). Carriers of variants in ABCG8 are reported to have elevated levels of plant sterols and hypercholesterolemia (Horenstein et al. 2013. PubMed ID: 23241408; Berge et al. 2000. PubMed ID: 11099417). Hemolytic anemia, stomatocyte formation, and macrothrombocytopenia are common hematologic findings in patients with sitosterolemia (Wang et al. 2014. PubMed ID: 24166850; Escolá-Gil et al. 2014. PubMed ID: 24821603). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.