Submissions for variant NM_000053.4(ATP7B):c.2621C>T (p.Ala874Val)

gnomAD frequency: 0.00001  dbSNP: rs121907994

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004055	SCV000626845	pathogenic	Wilson disease	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 874 of the ATP7B protein (p.Ala874Val). This variant is present in population databases (rs121907994, gnomAD 0.05%). This missense change has been observed in individuals with Wilson disease, with evidence of co-segregation with disease (PMID: 10544227, 10721669, 11775208, 12376745, 12544487, 16998622, 18156766, 21707886, 22735241). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3851). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP7B protein function. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22240481, 22692182). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004055	SCV000916640	pathogenic	Wilson disease	2018-11-16	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.2621C>T (p.Ala874Val) results in a non-conservative amino acid change in the P-type ATPase, A domain superfamily of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 246236 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (6.9e-05 vs 0.0054), allowing no conclusion about variant significance. The variant, c.2621C>T, has been reported in the literature in multiple individuals affected with Wilson Disease in both compound heterozygotes and homozygotes (Lee_2011, Dong_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function evaluating copper transport. The most pronounced variant effect results in 10-30% of normal copper transport rate activity (Huster_2012). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic x2, VUS x1). Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001091639	SCV001247798	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000004055	SCV001712292	pathogenic	Wilson disease	2021-05-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001091639	SCV001716163	pathogenic	not provided	2021-04-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001091639	SCV001781887	pathogenic	not provided	2020-04-09	criteria provided, single submitter	clinical testing	Published functional studies using the baculovirus expression system in Sf9 cells showed partial transport activity (Huster et al. 2012); 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: 30275481, 31980526, 31743419, 9452121, 30702195, 30655162, 29961769, 11775208, 21707886, 10544227, 12544487, 27398169, 16998622, 22735241, 11043508, 28515472, 16207219, 25704634, 23275100, 22308153, 22484412, 26782526, 19419418, 29381936, 28212618, 26269689, 22692182, 10721669, 22240481, 24253677, 26215059, 25988284, 12376745, 18156766)
Revvity Omics, Revvity	RCV000004055	SCV002021406	pathogenic	Wilson disease	2020-08-05	criteria provided, single submitter	clinical testing
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000004055	SCV002496401	pathogenic	Wilson disease	2022-01-01	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001091639	SCV002501994	likely pathogenic	not provided	2022-02-16	criteria provided, single submitter	clinical testing
Payam Genetics Center, General Welfare Department of North Khorasan Province	RCV000004055	SCV003914808	likely pathogenic	Wilson disease	2023-03-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004055	SCV004216314	pathogenic	Wilson disease	2024-03-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000004055	SCV004810142	likely pathogenic	Wilson disease	2024-04-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000004055	SCV004831416	pathogenic	Wilson disease	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 874 in the actuator domain 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). Functional studies have shown that this variant causes reduced protein expression, abnormal subcellular localization, and loss of copper transport activity (PMID: 22240481, 22692182). This variant has been reported in individuals affected with Wilson disease (PMID: 10544227, 10721669, 11043508, 12376745, 12544487, 16998622, 18156766, 21645214, 21707886, 22735241, 26269689, 25988284, 27022412, 27398169, 28212618, 29381936, 30702195, 31980526, 33763395). In many of these individuals, this variant was reported in the compound heterozygous state (PMID: 12376745, 21645214, 28212618, 29381936, 30702195, 31743419, 33763395) or homozygous state (PMID: 10721669, 18156766, 21645214, 22735241, 30702195). This variant has been identified in 17/249574 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000004055	SCV004847838	pathogenic	Wilson disease	2020-06-11	criteria provided, single submitter	clinical testing	The p.Ala874Val variant in ATP7B has been previously reported in many individuals with Wilson disease, including at least 2 compound heterozygotes and >10 compound heterozygotes, and segregated in at least 1 affected sibling (Chen 2019, Dong 2016, Kusuda 2000, Mihaylova 2012, Park 2009, Takeshita 2002, Tatsumi 2011, Yamaguchi 1998, Yoo 2002). It has been identified in 0.04% (8/17978) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this is low enough to be consistent with a recessive allele frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, an in vitro functional study indicates that this variant results in reduced copper transport activity (Huster 2012). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PS3_Supporting, PP1, PP4.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000004055	SCV005417845	pathogenic	Wilson disease		criteria provided, single submitter	clinical testing	PS3_Supporting+PM2_Supporting+PM3_VeryStrong+PP4
OMIM	RCV000004055	SCV000024221	pathogenic	Wilson disease	2009-04-01	no assertion criteria provided	literature only
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000004055	SCV000267218	uncertain significance	Wilson disease	2016-03-18	flagged submission	reference population
Counsyl	RCV000004055	SCV000487224	pathogenic	Wilson disease	2016-10-28	no assertion criteria provided	clinical testing
SingHealth Duke-NUS Institute of Precision Medicine	RCV000004055	SCV000853123	likely pathogenic	Wilson disease	2017-06-07	no assertion criteria provided	curation
Natera, Inc.	RCV000004055	SCV001459723	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing