ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2930C>T (p.Thr977Met) (rs72552255)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029359 SCV000052006 pathogenic Wilson disease 2019-10-28 criteria provided, single submitter clinical testing Variant summary: ATP7B c.2930C>T (p.Thr977Met) 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 8.4e-05 in 249606 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (8.4e-05 vs 0.0054), allowing no conclusion about variant significance. c.2930C>T has been reported in the literature in multiple individuals (both compound heterozygous and homozygous state) affected with Wilson Disease (e.g. Loudianos_1998, Vrabelova_2005, Aggarwal_2013). These data indicate that the variant is very likely to be associated with disease. In yeast complementation assays, based on the ability of ATP7B to complement the high-affinity iron-uptake deficiency of the yeast mutant ccc2, the variant resulted in a nonfunctional protein that is completely unable to complement ccc2 mutant yeast (Forbes_1998). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790662 SCV000225744 pathogenic not provided 2016-01-05 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000029359 SCV000593531 pathogenic Wilson disease 2016-06-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000029359 SCV000611171 pathogenic Wilson disease 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000029359 SCV000626847 pathogenic Wilson disease 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 977 of the ATP7B protein (p.Thr977Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs72552255, ExAC 0.01%). This variant has been reported in individuals and families affected with Wilson disease with strong evidence of segregation (PMID: 8938442, 11857545, 17272994, 18483695, 21610751, 22774841). In the homozygous state it has been associated with early liver disease (PMID: 20517649, 21682854, 23551039). ClinVar contains an entry for this variant (Variation ID: 35710). Experimental studies have shown that this missense change is not able to rescue ATP7B-null yeast cells (PMID: 9837819). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000029359 SCV001157760 pathogenic Wilson disease 2018-07-25 criteria provided, single submitter clinical testing The ATP7B c.2930C>T; p.Thr977Met variant (rs72552255), is reported in the literature in multiple individuals and families affected with Wilson disease (Chabik 2014, Dong 2016, Firneisz 2002, Loudianos 1998, Waldenstrom 1996, Weiss 2010). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 35710), and is found in the general population with an overall allele frequency of 0.009% (25/277122 alleles) in the Genome Aggregation Database. Functional analyses of the variant protein shows that it fails to rescue a knockout yeast cell line (Forbes 1998). The threonine at codon 977 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Chabik et al. Concordance rates of Wilson's disease phenotype among siblings. J Inherit Metab Dis. 2014 Jan;37(1):131-5. Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. Firneisz G et al. Common mutations of ATP7B in Wilson disease patients from Hungary. Am J Med Genet. 2002 Feb 15;108(1):23-8. Forbes and Cox Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant? Am J Hum Genet. 1998 Dec;63(6):1663-74. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. Waldenstrom et al. Efficient detection of mutations in Wilson disease by manifold sequencing. 1996 Nov 1;37(3):303-9. Weiss et al. Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S233-40
Myriad Women's Health, Inc. RCV000029359 SCV001193794 pathogenic Wilson disease 2020-01-06 criteria provided, single submitter clinical testing NM_000053.3(ATP7B):c.2930C>T(T977M) is classified as pathogenic in the context of Wilson disease. Sources cited for classification include the following: PMID 23518715, 9837819 and 8938442. Classification of NM_000053.3(ATP7B):c.2930C>T(T977M) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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