ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3007G>A (p.Ala1003Thr) (rs201497300)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169133 SCV000220347 likely pathogenic Wilson disease 2014-05-23 criteria provided, single submitter literature only
Invitae RCV000169133 SCV000626849 pathogenic Wilson disease 2020-07-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1003 of the ATP7B protein (p.Ala1003Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs201497300, ExAC 0.02%). This variant has been described as a common Wilson disease mutation in different populations (PMID: 23789284, 26799313, 16791614). It has been reported as homozygous or in combination with other ATP7B variants in multiple individuals affected with Wilson disease (PMID: 21610751, 12885331, 2679931, Invitae) and observed to segregate with the disease in a Lebanese family (PMID: 25390358). ClinVar contains an entry for this variant (Variation ID: 188802). A structural modeling analysis specifically for the ATP7B gene (PMID: 22692182), suggests that this amino acid position is likely to be sensitive to change, although this analysis has not been confirmed by functional studies. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169133 SCV001362724 pathogenic Wilson disease 2019-11-22 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3007G>A (p.Ala1003Thr) 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 4.6e-05 in 240334 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (4.6e-05 vs 0.0054). c.3007G>A has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Wilson Disease (e.g. Ljubic_2016). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions (evaluation after 2014) cite the variant likely pathogenic (1x) and pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000169133 SCV001474602 pathogenic Wilson disease 2019-10-10 criteria provided, single submitter clinical testing The ATP7B c.3007G>A; p.Ala1003Thr variant (rs201497300) is reported in the literature in multiple individuals with Wilson disease (Loudianos 1998, Moller 2011, Stalke 2018, Tomic 2013, Usta 2014). It has been reported in trans to a pathogenic frameshift variant and shown to co-segregate with disease (Usta 2014). A different variant as this codon (Ala1003Val) is also reported in association with Wilson disease (Guggilla 2015, Loudianos 1999). The p.Ala1003Thr variant is reported in ClinVar (Variation ID: 188802). It is found in the Genome Aggregation Database with a low overall allele frequency of 0.005% (11/240334 alleles), indicating it is not a common polymorphism. The alanine at codon 1003 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Guggilla SR et al. Spectrum of mutations in the ATP binding domain of ATP7B gene of Wilson Disease in a regional Indian cohort. Gene. 2015 Sep 10;569(1):83-7. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. Loudianos G et al. Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations. J Med Genet. 1999 Nov;36(11):833-6. Moller LB et al. Clinical presentation and mutations in Danish patients with Wilson disease. Eur J Hum Genet. 2011 Sep;19(9):935-41. Stalke A et al. Diagnosis of monogenic liver diseases in childhood by next-generation sequencing. Clin Genet. 2018 Mar;93(3):665-670. Tomic A et al. Mutational analysis of ATP7B gene and the genotype-phenotype correlation in patients with Wilson's disease in Serbia. Vojnosanit Pregl. 2013 May;70(5):457-62. Usta J et al. Phenotype-genotype correlation in Wilson disease in a large Lebanese family: association of c.2299insC with hepatic and of p. Ala1003Thr with neurologic phenotype. PLoS One. 2014 Nov 12;9(11):e109727.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415237 SCV000492605 likely pathogenic Epileptic encephalopathy 2016-03-15 no assertion criteria provided clinical testing
Natera, Inc. RCV000169133 SCV001459710 pathogenic Wilson disease 2020-09-16 no assertion criteria provided clinical testing

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