rs756029120
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000053.4(ATP7B):c.3517G>A(p.Glu1173Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1173G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000053.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.3517G>A | p.Glu1173Lys | missense_variant | 16/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.3517G>A | p.Glu1173Lys | missense_variant | 16/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249590Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135408
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461888Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 727244
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:10
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 19, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Nov 06, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 16, 2018 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 13, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 04, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 31, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at