ClinVar Genomic variation as it relates to human health

Variant summary: The ATP7B c.3796G>A (p.Gly1266Arg) variant involves the alteration of a highly conserved nucleotide. The variant is located within the putative ATP binding site of the conserved P-type ATPase Cu-like domain and 5/5 in silico tools predict a damaging outcome for this variant. These predictions were confirmed by the functional study, Huster_2012, where G1266R was shown to markedly affect copper transport and abolish catalytic phosphorylation. This variant was found in 6/120738 control chromosomes at a frequency of 0.000049, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant was identified in multiple affected individuals in compound heterozygosity with clinically and biochemically confirmed Wilsons disease (WD). The codon Gly1266 appears to be a mutational hot-spot, as other alteration, such as p.G1266E, p.G1266W and p.G1266V, have been reported in patients with WD. Taken together, this variant is classified as Pathogenic.

Published functional studies demonstrate damaging effects, including low copper uptake and inactive catalytic phosphorylation (Huster et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In addition, in silico splice predictors suggest this variant may lead to abnormal gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21610751, 11243728, 7626145, 10502777, 22692182, 22240481, 24253677, 23518715)

The ATP7B c.3796G>A; p.Gly1266Arg variant (rs121907992) is reported in the literature in several individuals affected with Wilson disease (Butler 2001, Moller 2011, Thomas 1995). This variant is also reported in ClinVar (Variation ID: 3849), and is found in the general population with an overall allele frequency of 0.0036% (10/280988 alleles) in the Genome Aggregation Database. The glycine at codon 1266 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.968). In vitro functional analyses demonstrate a loss of protein function (Huster 2012). Additionally, other amino acid substitutions at this codon (Glu, Trp, Val) have been reported in individuals with Wilson disease and are considered pathogenic (Li 2013, Pena-Quintana 2012, Shah 1997). Based on available information, this variant is considered to be pathogenic. References: Butler P et al. Molecular diagnosis of Wilson disease. Mol Genet Metab. 2001 Mar;72(3):223-30. PMID: 11243728. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. PMID: 22240481. Li K et al. Mutational analysis of ATP7B in north Chinese patients with Wilson disease. J Hum Genet. 2013 Feb;58(2):67-72. PMID: 23235335. Moller LB et al. Clinical presentation and mutations in Danish patients with Wilson disease. Eur J Hum Genet. 2011 Sep;19(9):935-41. PMID: 21610751. Pena-Quintana L et al. Manifestations and evolution of Wilson disease in pediatric patients carrying ATP7B mutation L708P. J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):48-54. PMID: 21832955. Shah AB et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997 Aug;61(2):317-28. PMID: 9311736. Thomas GR et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995 Feb;9(2):210-7. PMID: 7626145.

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1266 of the ATP7B protein (p.Gly1266Arg). This variant is present in population databases (rs121907992, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 7626145, 11243728, 21610751). ClinVar contains an entry for this variant (Variation ID: 3849). 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 ATP7B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22240481, 22692182). For these reasons, this variant has been classified as Pathogenic.

ATP7B: PM3:Strong, PS1, PM1, PM2, PM5, PP3, PP4, PS3:Supporting

The p.Gly1266Arg variant in ATP7B has been previously reported in >20 patients with Wilson disease, including at least 8 compound heterozygotes and 1 homozygote, and segregated in an affected relative (Butler 2001, Coffey 2013, Curtis 1999, Moller 2011, Thomas 1995). This variant has also been reported in ClinVar (Variation ID 3849) and is present in 0.01% (3/24200) of African and 0.005% (7/128724) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. Computational prediction tools and conservation analysis suggest an impact to the protein. Furthermore, an in vitro study suggested an impact on protein function (Huster 2012). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP1, PP3, PP4, PS3_Supporting.

This missense variant replaces glycine with arginine at codon 1266 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant disrupts copper uptake and transport (PMID: 22240481, 22692182). This variant has been reported in individuals affected with Wilson disease (PMID: 10502777, 11243728, 21610751, 23518715, 36096368). In some of these affected individuals, this variant has been determined to be compound heterozygous with another pathogenic variant in the same gene, while heterozygous carriers of this variant were determined to be unaffected. These data indicate that this variant contributes to Wilson disease in an autosomal recessive manner. This variant has been identified in 10/280988 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

PP1, PP3, PP4, PM2_moderate, PS3, PS4_moderate