Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Illumina Laboratory Services, |
RCV001110330 | SCV001267752 | uncertain significance | Wilson disease | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Labcorp Genetics |
RCV001110330 | SCV001412635 | uncertain significance | Wilson disease | 2022-10-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1111 of the ATP7B protein (p.Gly1111Asp). This variant is present in population databases (rs182659444, gnomAD 0.1%). This missense change has been observed in individual(s) with ATP7B-related conditions (PMID: 12515040, 19514071, 30232804). ClinVar contains an entry for this variant (Variation ID: 881368). 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. 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. |
Genome- |
RCV001110330 | SCV001810288 | uncertain significance | Wilson disease | 2021-07-22 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002282457 | SCV002572257 | uncertain significance | not specified | 2022-08-23 | criteria provided, single submitter | clinical testing | Variant summary: ATP7B c.3332G>A (p.Gly1111Asp) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 249578 control chromosomes (gnomAD). This frequency is not higher than the maximum predicted for a pathogenic variant in ATP7B causing Wilson Disease (0.0054), allowing no conclusion about variant significance. c.3332G>A has been reported in the literature in heterozygous state in individuals with ATP7B-related conditions (e.g. Vrabelova_2005, Cocco_2009, Ferenci_2019). These reports do not provide unequivocal conclusions about association of the variant with Wilson Disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Fulgent Genetics, |
RCV001110330 | SCV002787132 | uncertain significance | Wilson disease | 2024-04-20 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV001110330 | SCV003834483 | uncertain significance | Wilson disease | 2020-08-27 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV001110330 | SCV004361969 | uncertain significance | Wilson disease | 2022-08-02 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with aspartic acid at codon 1111 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). Functional studies have shown this variant impaired intracytoplasmic copper transport (PMID: 15967699, 19514071). This variant has been reported in individuals affected with Wilson disease (PMID: 12515040, 15967699) or acquired hepatocerebral degeneration (PMID: 19514071). This variant has been identified in 47/280988 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. |
All of Us Research Program, |
RCV001110330 | SCV004845381 | uncertain significance | Wilson disease | 2024-09-23 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with aspartic acid at codon 1111 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). Functional studies have shown this variant impaired intracytoplasmic copper transport (PMID: 15967699, 19514071). This variant has been reported in individuals affected with Wilson disease (PMID: 12515040, 15967699) or acquired hepatocerebral degeneration (PMID: 19514071). This variant has been identified in 47/280988 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. |
Ambry Genetics | RCV004032153 | SCV004913439 | uncertain significance | Inborn genetic diseases | 2022-04-18 | criteria provided, single submitter | clinical testing | The c.3332G>A (p.G1111D) alteration is located in exon 15 (coding exon 15) of the ATP7B gene. This alteration results from a G to A substitution at nucleotide position 3332, causing the glycine (G) at amino acid position 1111 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
Breakthrough Genomics, |
RCV004693663 | SCV005192153 | uncertain significance | not provided | criteria provided, single submitter | not provided | ||
Natera, |
RCV001110330 | SCV002086816 | uncertain significance | Wilson disease | 2020-02-14 | no assertion criteria provided | clinical testing | |
Prevention |
RCV003938458 | SCV004758591 | uncertain significance | ATP7B-related disorder | 2024-01-16 | no assertion criteria provided | clinical testing | The ATP7B c.3332G>A variant is predicted to result in the amino acid substitution p.Gly1111Asp. This variant was reported in an individual undergoing genetic testing for Wilson disease (Vrabelova et al. 2005. PubMed ID: 15967699). This variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |