ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3443T>C (p.Ile1148Thr) (rs60431989)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727509 SCV000709306 pathogenic not provided 2017-06-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000023582 SCV000916630 pathogenic Wilson disease 2018-05-10 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3443T>C (p.Ile1148Thr) results in a non-conservative amino acid change located in the ATP-loop functional domain region in the encoded protein sequence (Luoma_2010). 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 4e-05 in 277638 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (4e-05 vs 5.40e-03), allowing no conclusion about variant significance. The variant, c.3443T>C, has been reported in the literature in multiple individuals affected with Wilson Disease, in trans with other pathogenic variants (Loudianos_1998, Haas_1999, Gu_2003, Abdelghaffar_2008, Mak_2008, Panagiotakaki_2004). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Luoma_2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000023582 SCV000942645 pathogenic Wilson disease 2020-01-08 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1148 of the ATP7B protein (p.Ile1148Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs60431989, ExAC 0.05%). This variant has been observed to segregate with Wilson disease in a family (PMID: 21796144). It has also been reported as homozygote or in combination with another ATP7B variant in several unrelated individuals affected with Wilson disease (PMID: 23843956, 28212618). ClinVar contains an entry for this variant (Variation ID: 3863, 37122). Experimental studies have shown that this missense change disrupts ATP7B protein function (PMID: 20333758). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000023582 SCV001158017 pathogenic Wilson disease 2018-11-15 criteria provided, single submitter clinical testing The ATP7B c.3443T>C; p.Ile1148Thr variant (rs60431989), is reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Wilson disease (Dedoussis 2005, Gu 2013, Panagiotakaki 2004, Yu 2017). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 37122), and is found in the East Asian population with an allele frequency of 0.041% (8/19,538 alleles) in the Genome Aggregation Database. The isoleucine at codon 1148 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Ile1148Thr variant is considered to be pathogenic. References: Dedoussis GV et al. Wilson disease: high prevalence in a mountainous area of Crete. Ann Hum Genet. 2005 May;69(Pt 3):268-74. Gu S et al. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. PLoS One. 2013 Jul 2;8(7):e66526. Panagiotakaki E et al. Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A. 2004 Dec 1;131(2):168-73. Yu H et al. Clinical features and outcome in patients with osseomuscular type of Wilson's disease. BMC Neurol. 2017 Feb 17;17(1):34.
OMIM RCV000023582 SCV000044873 pathogenic Wilson disease 2011-09-01 no assertion criteria provided literature only
Counsyl RCV000023582 SCV000220681 pathogenic Wilson disease 2017-02-27 no assertion criteria provided clinical testing

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