ClinVar Genomic variation as it relates to human health

Variant summary: ATP7B c.3671G>T (p.Arg1224Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 7.9e-05 in 277238 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (7.9e-05 vs 0.0054), allowing no conclusion about variant significance. The variant, c.3671G>T, has been reported in the literature in an individual presenting with "Steatosis hepatitis, elevated liver enzymes, normal CP, urinary copper, cMRI," who was a compound heterozygote for the variant and c.*16G>A (internally classified as a VUS - possibly benign)(Stalke_2018). This report does not provide unequivocal conclusion about an association of the variant with Wilson Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1224 of the ATP7B protein (p.Arg1224Leu). This variant is present in population databases (rs532177115, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of ATP7B-related conditions (PMID: 28776642). ClinVar contains an entry for this variant (Variation ID: 632662). 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 not expected to disrupt ATP7B protein function with a negative predictive value of 80%. 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.

This missense variant replaces arginine with leucine at codon 1224 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported with a co-occurring variant in an individual exhibiting atypical symptoms for Wilson Disease (PMID: 28776642). This variant has been identified in 25/280998 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Identified in a patient with steatosis hepatitis who was also heterozygous for a likely benign variant in ATP7B; this patient also had normal ceruloplasmin and urinary copper (PMID: 28776642); Not observed at significant frequency in large population cohorts (gnomAD); 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: 30097039, 28776642)