Submissions for variant NM_000053.4(ATP7B):c.1555G>A (p.Val519Met)

gnomAD frequency: 0.00041  dbSNP: rs192957846

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000996142	SCV001150663	uncertain significance	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001111162	SCV001268685	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193095	SCV001361700	uncertain significance	not specified	2023-03-09	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.1555G>A (p.Val519Met) results in a conservative amino acid change located in the fifth copper ion-binding domain (IPR006122) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 249396 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (0.0006 vs 0.0054), allowing no conclusion about variant significance. However the occurrence of the homozygous individual might suggest that the variant is benign. The variant, V519M, has been reported in the literature from a newborn blood sample with low ceruloplasmin value (i.e. in the low normal range, according to the authors), but further information was not provided on this case (Kroll 2006). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001111162	SCV001412837	uncertain significance	Wilson disease	2022-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 519 of the ATP7B protein (p.Val519Met). This variant is present in population databases (rs192957846, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. ClinVar contains an entry for this variant (Variation ID: 807938). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000996142	SCV001714459	uncertain significance	not provided	2019-10-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001111162	SCV002027174	uncertain significance	Wilson disease	2021-09-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001111162	SCV004362496	uncertain significance	Wilson disease	2022-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 519 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 been reported in an individual affected with Wilson disease (PMID: 16644258). This variant has been identified in 163/280786 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.
Natera, Inc.	RCV001111162	SCV002087871	uncertain significance	Wilson disease	2020-01-14	no assertion criteria provided	clinical testing