ClinVar Genomic variation as it relates to human health

The ATP7B c.1993A>G; p.Met665Val variant (rs146303208), to our knowledge, is not described in the medical literature but contains and entry in ClinVar (Variation ID: 495404). It is observed in the general population at an overall frequency of 0.066% (184/280588 alleles) in the Genome Aggregation Database. The methionine at codon 665 is moderately conserved, but computational algorithms (PolyPhen-2: benign, SIFT: damaging) predict conflicting effects of this variant on protein structure/function. Another variant at this codon (c.1995G>A; p.Met665Ile) has been described in association with Wilson disease and is considered pathogenic (see link to Wilson disease mutation database). However, due to limited information regarding the p.Met665Val variant, its clinical significance cannot be determined with certainty. REFERENCES Wilson Disease Mutation Database: http://www.wilsondisease.med.ualberta.ca/search3.asp?a=a

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.

Variant summary: ATP7B c.1993A>G (p.Met665Val) results in a conservative amino acid change located in the heavy metal associated domain 5 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 0.00068 in 249212 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00068 vs 0.0054), allowing no conclusion about variant significance. c.1993A>G has been reported in the literature in at-least one individual affected with Schizophrenia in a study examining the hypothesis that psychiatric populations are enriched for pathogenic variants associated with selected inborn errors of metabolism (IEMs) (Sriretnakumar_2019). This report does not provide unequivocal conclusions about association of the variant with Wilson Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6; likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces methionine with valine at codon 665 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with Wilson disease in the literature. This variant has been identified in 184/280588 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.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Described using alternate nomenclature (c.1660A>G M554V) in a cohort of individuals with psychiatric symptoms in whom a second variant in ATP7B was not described (PMID: 30556376); 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: 39000354, 37937776, 30556376)

This missense variant replaces methionine with valine at codon 665 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with Wilson disease in the literature. This variant has been identified in 184/280588 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.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).