ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2804C>T (p.Thr935Met) (rs750019452)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169002 SCV000220142 likely pathogenic Wilson disease 2014-03-03 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169002 SCV000694431 pathogenic Wilson disease 2016-12-21 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.2804C>T (p.Thr935Met) variant involves the alteration of a conserved nucleotide and is located in the transmembrane 5 domain of the ATP7B protein, known to be associated with copper excretion (ACMG PM1). 5/5 in silico tools predict a damaging outcome for this variant (ACMG PP3). This variant was found in 22/121398 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0023218 (20/8614) which could represent carriers of Wilson Disease (ACMG PM2). This variant has been reported in numerous WD patients both as homozygotes and as compound heterozygotes, mainly of East Asian origin (ACMG PM3). A recently published study reported an odds ratio of 77.044 (95% CI 10.716-553.9) for this variant based on Its prevalence in affected individuals as compared to controls (ACMG PS4). In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Functional study with stable transfected CHO cell showed variant with comparable level of CuCl2-induced copper overloading of CHO cells. The influence of ATP7B on copper elimination by variant of interest is minimal, and T935M mutation maintained the subcellular localization or trafficking of ATP7B protein. Taken together, even though the functional effect of variant is not obvious, this variant fulfills the criteria required to be classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000169002 SCV000731403 pathogenic Wilson disease 2020-03-29 criteria provided, single submitter clinical testing The p.Thr935Met variant in ATP7B has been reported in at least 10 compound heterozygous individuals with clinical features of Wilson disease and is one of the most common variants detected in Asian patients with this disorder (Wu 2001, Gu 2003, and Chen 2014). It has also been reported by other clinical laboratories in ClinVar (Variation ID 188713). This variant has been identified in 0.2% (46/19536) of East Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies support an impact on protein function (Zhu 2015) and computational prediction tools and conservation analyses suggest are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PS3_Supporting.
Invitae RCV000169002 SCV000823768 pathogenic Wilson disease 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 935 of the ATP7B protein (p.Thr935Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs750019452, ExAC 0.2%). This variant has been observed to be homozygous or in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 11775208, 26483271, 14986826, 27022412, 16649058) and it is commonly found in some East Asian populations (PMID: 18568852, 18034201). ClinVar contains an entry for this variant (Variation ID: 188713). Experimental studies have shown that this missense change impairs cellular copper excretion in vitro (PMID: 26032686). For these reasons, this variant has been classified as Pathogenic.

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