rs121907994
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000053.4(ATP7B):c.2621C>T(p.Ala874Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,614,060 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. A874E) has been classified as Uncertain significance.
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.2621C>T | p.Ala874Val | missense_variant | 11/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.2621C>T | p.Ala874Val | missense_variant | 11/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000681 AC: 17AN: 249574Hom.: 0 AF XY: 0.0000739 AC XY: 10AN XY: 135402
GnomAD4 exome AF: 0.0000588 AC: 86AN: 1461892Hom.: 0 Cov.: 35 AF XY: 0.0000564 AC XY: 41AN XY: 727248
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:14Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2009 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Provincial Medical Genetics Program of British Columbia, University of British Columbia | Jan 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Payam Genetics Center, General Welfare Department of North Khorasan Province | Mar 01, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 05, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | 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. - |
Uncertain significance, flagged submission | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 16, 2018 | 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Oct 28, 2016 | - - |
Likely pathogenic, no assertion criteria provided | curation | SingHealth Duke-NUS Institute of Precision Medicine | Jun 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 11, 2020 | 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. - |
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Feb 16, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 20, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 09, 2020 | 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) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at