NM_000053.4:c.2332C>G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000053.4(ATP7B):c.2332C>G(p.Arg778Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,890 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. R778L) has been classified as 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.2332C>G | p.Arg778Gly | missense_variant | Exon 8 of 21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249436Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135340
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727246
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:10Other:1
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This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 778 of the ATP7B protein (p.Arg778Gly). This variant is present in population databases (rs137853284, gnomAD 0.002%). This missense change has been observed in individual(s) with Wilson disease (PMID: 20517649, 21682854, 23333878). ClinVar contains an entry for this variant (Variation ID: 156283). 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%. This variant disrupts the p.Arg778 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11243728, 11479773, 16998622, 17160357, 23518715). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
The p.Arg778Gly variant in ATP7B has been reported in several individuals with Wilson disease, including at least 4 homozygous and 3 compound heterozygous individuals (AbdelGhaffar 2011, Bruha 2011, Coffey 2013, Figus 1995, Gromadzka 2005, Petrasek 2007, Simsek Papur 2013, Vrabelova 2005, Weiss 2010). It has also been identified in 0.001% (2/113168) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is low enough to be consistent with a recessive allele frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, a pathogenic variant at the same position, p.Arg778Trp, has also been reported in many individuals with Wilson disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PM3_Strong, PM2, PM5, PP3, PP4. -
This missense variant replaces arginine with glycine at codon 778 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). Although functional studies have not been reported for this variant, it alters a conserved arginine residue in the transmembrane M2 domain of the ATP7B protein (a.a. 764 - 784), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). This variant has been reported in many individuals affected with Wilson disease (PMID: 8533760, 9801873, 11216666, 12515040, 16207219, 16283883, 16998622, 17154398, 17272994, 18371106, 20517649, 20958917, 21406212, 21682854, 22093921, 22677543, 23333878, 23518715, 24517292, 26215059, 27935710, 30230192, 31708252, 33159804, 34400371). In a number of these individuals, this variant was reported in the compound heterozygous state or the homozygous state (PMID: 16283883, 17272994, 20517649, 22093921, 23518715, 24517292). Different missense variants occurring at the same codon, p.Arg778Leu, p.Arg778Trp, and p.Arg778Gln, are known to cause disease (ClinVar variation ID: 3852, 456553, 550914), indicating that arginine at this position is important for ATP7B protein function. This variant has been identified in 2/249436 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Variant summary: ATP7B c.2332C>G (p.Arg778Gly) results in a non-conservative amino acid change in 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 8.1e-06 in 246100 control chromosomes (gnomAD). c.2332C>G has been reported in the literature in multiple individuals affected with Wilson Disease (Ferenci_2014). These data indicate that the variant is very likely to be associated with disease. In addition, another variant, c.2332C>T (p.Arg778Trp) affecting the same codon has been classified as pathogenic, therefore, suggesting the importance of this location for ATP7B protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
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not provided Pathogenic:2
Not observed at significant frequency in large population cohorts (gnomAD); 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: 17272994, 8533760, 34400371, 24253677, 22692182, 9801873, 11216666, 16207219, 31708252, 32043565, 34426522, 33098801, 35872528, 33159804, 16283883) -
ATP7B: PM3:Very Strong, PM1, PM2, PM5, PP3, PP4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at