Submissions for variant NM_000053.4(ATP7B):c.1993A>G (p.Met665Val)

gnomAD frequency: 0.00053  dbSNP: rs146303208

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001003423	SCV000694410	uncertain significance	not specified	2022-03-18	criteria provided, single submitter	clinical testing	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.
Invitae	RCV001001851	SCV001015509	likely benign	Wilson disease	2024-01-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587250	SCV001150660	uncertain significance	not provided	2019-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001851	SCV001159555	uncertain significance	Wilson disease	2019-03-06	criteria provided, single submitter	clinical testing	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
Illumina Laboratory Services, Illumina	RCV001001851	SCV001267851	uncertain significance	Wilson disease	2018-01-13	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000587250	SCV001714451	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001001851	SCV001977175	uncertain significance	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000587250	SCV002503994	uncertain significance	not provided	2023-04-07	criteria provided, single submitter	clinical testing	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 (Sriretnakumar V et al., 2019); 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: 30556376)
Mendelics	RCV001003423	SCV002517904	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002530885	SCV003759210	likely benign	Inborn genetic diseases	2021-11-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Revvity Omics, Revvity	RCV001001851	SCV003834482	uncertain significance	Wilson disease	2022-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001001851	SCV004362491	uncertain significance	Wilson disease	2022-09-23	criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV003905504	SCV004718524	likely benign	ATP7B-related condition	2022-04-25	criteria provided, single submitter	clinical testing	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).
Natera, Inc.	RCV001001851	SCV001456182	uncertain significance	Wilson disease	2020-04-15	no assertion criteria provided	clinical testing