ClinVar Genomic variation as it relates to human health

This variant was identified with NM_000053.4:c.1285+5G>T, phase is unknown. Both variants were reported as secondary findings in a patient without Wilson associated symptoms Criteria applied: PM3_STR, PS3_MOD, PM5, PM2_SUP, PP3

Published functional studies demonstrate a damaging effect (Lee et al., 2011); 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: 24253677, 22692182, 17949296, 26215059, 22484412, 21645214, 23333878, 32231684, 30275481, 23089210, 15147237, 27022412, 23235335, 34470610, 34620762, Rosa[article]2021)

The ATP7B c.3451C>T variant is predicted to result in the amino acid substitution p.Arg1151Cys. This variant was reported in multiple individuals with Wilson disease (Lepori et al. 2007. PubMed ID: 17949296, Lee et al. 2011. PubMed ID: 21645214, Hua et al. 2016. PubMed ID: 27398169). It is unclear based on the literature if these variants were seen in the homozygous or compound heterozygous state. However, it was reported with a second pathogenic variant in one patient with clinical and biochemical features consistent with Wilson disease (Simsek Papur et al. 2013. PubMed ID: 23333878). In vitro functional characterization suggests that this variant is deleterious (Lee et al. 2011. PubMed ID: 21645214). Of note, two additional missense variants affecting this residue have been reported in association with Wilson disease with unclear evidence of pathogenicity (p.Arg1151His and p.Arg1151Gly; Morgan et al. 2004. PubMed ID: 15205462, Loudianos et al. 1999. PubMed ID: 10544227, Dong et al. 2016. PubMed ID: 27022412). This variant is located in exon 16, where a large number of ATP7B variants have been associated with disease (Li. 2021. PubMed ID: 34470610). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-52515322-G-A). Of note, this variant was also detected in a patient who carried two additional likely pathogenic/pathogenic variants in this gene. Overall, the collective evidence suggests that this variant is likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1151 of the ATP7B protein (p.Arg1151Cys). This variant is present in population databases (rs755554442, gnomAD 0.02%). This missense change has been observed in individual(s) with Wilson disease (PMID: 17949296, 21645214, 23333878, 27398169). ClinVar contains an entry for this variant (Variation ID: 188839). 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: 21645214). This variant disrupts the p.Arg1151 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10544227, 15205462, 30655162). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

This missense variant replaces arginine with cysteine at codon 1151 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant alters a conserved arginine residue in the ATP nucleotide-binding domain of the ATP7B protein (a.a. 1032 - 1196), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). Experimental studies have shown that this variant results in abnormal function in yeast complementation and growth assays (PMID: 21645214). This variant has been reported in numerous individuals affected with Wilson disease (PMID: 17949296, 21645214, 22484412, 23235335, 23333878, 26215059, 27398169, 27022412, 34428338, 34620762; DOI:10.46531/sinapse/AO/210033/2021). In at least one of these affected individuals, this variant has been determined to be compound heterozygous with another pathogenic variant in the same gene, indicating that this variant contributes to Wilson disease in an autosomal recessive manner (PMID: 23333878, 26215059). This variant has been identified in 14/249588 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

The p.Arg1151Cys variant in ATP7B has been reported in more than 5 individuals with Wilson disease (at least 3 in the compound heterozygous state)(Lepori 2007 PMID: 17949296, Lee 2011 PMID:21645214, Papur 2013 PMID: 23333878, Hua 2016 PMID: 27398169, Dong 2016 PMID: 27022412). This variant has also been reported in ClinVar (Variation ID: 188839). It has also been identified in 1/4822 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Lee 2011 PMID: 21645214). Other variants involving this codon (including the likely pathogenic p.Arg1151His) have been identified in individuals with Wilson disease. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PM2_supporting, PP3, PM5, PS3_Supporting, PM3.

Variant interpreted as Likely pathogenic and reported on 04-18-2019 by Lab or GTR ID 507240. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.