Submissions for variant NM_000053.4(ATP7B):c.3517G>A (p.Glu1173Lys)

gnomAD frequency: 0.00002  dbSNP: rs756029120

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169445	SCV000220864	likely pathogenic	Wilson disease	2014-11-06	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169445	SCV000626855	pathogenic	Wilson disease	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1173 of the ATP7B protein (p.Glu1173Lys). This variant is present in population databases (rs756029120, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 17680703, 23275100, 23843956, 27022412; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189050). 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 expected to disrupt ATP7B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 20333758). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169445	SCV000694448	pathogenic	Wilson disease	2017-04-13	criteria provided, single submitter	clinical testing	Variant summary: The ATP7B c.3517G>A (p.Glu1173Lys) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the HAD-like domain and P-type ATPase, cytoplasmic domain N (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database ExAC and control cohorts in the literature at a frequency of 0.0000082 (1/121248 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). Multiple publications have reported the variant in Wilson disease patients. One study that provided familial genotyping data to confirm inheritance of the variant of interest along with a second pathogenic allele (Lee_TP7B_JHG_2000). One clinical diagnostic laboratory and several reputable databases have classified this variant as likely pathogenic or pathogenic. Taken together, this variant is classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV000169445	SCV000915633	pathogenic	Wilson disease	2018-08-16	criteria provided, single submitter	clinical testing	The ATP7B c.3517G>A (p.Glu1173Lys) missense variant has been reported in seven studies in which it is found in a compound heterozygous state in at least seven patients and in a heterozygous state in at least eight patients, all with Wilson disease (Loudianos et al. 1999; Lee et al. 2000; Chappuis et al. 2007; Geng et al. 2013; Gu et al. 2013; Cheng et al. 2014; Dong et al. 2016). In at least one family in which the patient was compound heterozygous for the p.Glu1173Lys variant and a missense variant, the unaffected sister and father were identified to be heterozygous for the p.Glu1173Lys variant while the unaffected mother was heterozygous for the other missense variant. This variant was absent from at least 77 controls and is reported at a frequency of 0.000012 in the total population from the Genome Aggregation Database. Based on the evidence, the p.Glu1173Lys variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Genome-Nilou Lab	RCV000169445	SCV001977251	likely pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169445	SCV002810891	pathogenic	Wilson disease	2022-01-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169445	SCV004216335	pathogenic	Wilson disease	2023-11-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000169445	SCV004238442	pathogenic	Wilson disease	2023-03-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000169445	SCV004845340	pathogenic	Wilson disease	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1173 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). This variant alters a conserved glutamic acid residue in the N domain of the ATP7B protein (a.a. 1032 - 1196), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 10544227, 11043508, 11405812, 11775208, 14986826, 17317524, 23275100, 23843956, 24718822, 27022412, 30702195), including in 1 individual in the homozygous state (PMID: 27022412) and in 10 individuals in the compound heterozygous state or in unknown phase with a second pathogenic variant in the ATP7B gene (PMID: 10544227, 11043508, 11775208, 17317524, 23275100, 23843956, 24718822, 30702195). This variant has been identified in 3/249590 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Natera, Inc.	RCV000169445	SCV001455586	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing