ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3694A>C (p.Thr1232Pro) (rs568009639)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670901 SCV000795814 likely pathogenic Wilson disease 2017-11-17 criteria provided, single submitter clinical testing
Invitae RCV000670901 SCV000956145 pathogenic Wilson disease 2018-08-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 1232 of the ATP7B protein (p.Thr1232Pro). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and proline. This variant is present in population databases (rs568009639, ExAC 0.009%). This variant has been observed in several unrelated individuals affected with Wilson disease (PMID: 15024742, 15952988) and to segregate with disease in one family (PMID: 15337266). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000670901 SCV001473293 likely pathogenic Wilson disease 2020-02-26 criteria provided, single submitter clinical testing 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.

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