rs568009639
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000053.4(ATP7B):āc.3694A>Cā(p.Thr1232Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,246 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1232I) 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 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.3694A>C | p.Thr1232Pro | missense_variant | 17/21 | ENST00000242839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP7B | ENST00000242839.10 | c.3694A>C | p.Thr1232Pro | missense_variant | 17/21 | 1 | NM_000053.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249572Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135406
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727248
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152352Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2AN XY: 74498
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:6
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 26, 2020 | The ATP7B c.3694A>C; p.Thr1232Pro variant (rs568009639) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with Wilson disease, and segregates with disease in at least one family (Coffey 2013, Deguti 2004, Margarit 2005, Velez-Pardo 2004). This variant is reported in ClinVar (Variation ID: 555144), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 1232 is moderately conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Based on available information, this variant is considered to be likely pathogenic. References: Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. Deguti MM et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398. Margarit E et al. Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet. 2005 Jul;68(1):61-8. Velez-Pardo C et al. New mutation (T1232P) of the ATP-7B gene associated with neurologic and neuropsychiatric dominance onset of Wilson's disease in three unrelated Colombian kindred. Neurosci Lett. 2004 Sep 9;367(3):360-4. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1232 of the ATP7B protein (p.Thr1232Pro). This variant is present in population databases (rs568009639, gnomAD 0.003%). This missense change has been observed in individual(s) with Wilson disease (PMID: 15024742, 15337266, 15952988). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 555144). 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 not expected to disrupt ATP7B protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 17, 2023 | This missense variant replaces threonine with proline at codon 1232 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in the homozygous state and in the compound heterozygous state in individuals affected with Wilson disease (PMID: 15024742, 15337266, 15952988, 23518715, 27992490, 33159804, 34400371, 34620762, 36096368, 36096368; DOI: 10.4172/lpma.1000228, 10.46531/sinapse/AO/210033/2021). This variant has been identified in 1/249572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 08, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at