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

gnomAD frequency: 0.00002  dbSNP: rs201497300

Total submissions: 15

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169133	SCV000626849	pathogenic	Wilson disease	2024-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1003 of the ATP7B protein (p.Ala1003Thr). This variant is present in population databases (rs201497300, gnomAD 0.007%). This missense change has been observed in individual(s) with Wilson disease (PMID: 2679931, 12885331, 16791614, 21610751, 23789284, 25390358, 26799313; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188802). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. 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.
Genome-Nilou Lab	RCV000169133	SCV001977287	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003311702	SCV004010243	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	ATP7B: PM3:Very Strong, PM2, PM5, PP3, PP4
Neuberg Centre For Genomic Medicine, NCGM	RCV000169133	SCV004176644	pathogenic	Wilson disease		criteria provided, single submitter	clinical testing	The observed missense c.3007G>Ap.Ala1003Thr variant in ATP7B gene has been reported in compound heterozygote/ homozygous state in individuals in multiple individuals affected with Wilson Disease Usta J,et. al., 2014;Ljubić H, et. al., 2016; Møller LB, et. al., 2011. It has also been observed to segregate with disease in related individuals. The p.Ala1003Thr variant is present with an allele frequency 0.004% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic/ Pathogenic multiple submission. The reference amino acid in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 1003 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove the pathogenicity for the variant, for these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169133	SCV004216382	pathogenic	Wilson disease	2024-01-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000169133	SCV004818663	pathogenic	Wilson disease	2023-12-01	criteria provided, single submitter	clinical testing	This variant is present in 11/240334 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant was detected in multiple affected individuals as homozygous or as compound heterozygous (in trans) with a likely pathogenic or pathogenic variant, which is consistent with autosomal recessive inheritance (PMID: 9671269, 10790207, 11243728, 11690702, 12885331, 17433323, 24661374, 26799313, 27022412, 27398169, 30120852). This variant is predicted to be deleterious by in silico analysis. This prediction has not been confirmed by functional studies.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169133	SCV004847817	pathogenic	Wilson disease	2020-06-11	criteria provided, single submitter	clinical testing	The p.Ala1003Thr variant in ATP7B has been reported in many individuals with Wilson disease, including at least 4 homozygotes and 12 compound heterozyotes, and it has segregated in 3 affected relatives (Aggarwal 2013, Butler 2001, Coffey 2013, Ferenci 2007, Kumar 2006, Ljubic 2016, Usta 2014). It has been identified in 8/108520 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Strong, PM2_Supporting, PP3, PP4.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000169133	SCV005368138	pathogenic	Wilson disease	2025-03-04	criteria provided, single submitter	clinical testing	Criteria applied: PM5_STR,PM1,PM3,PM2_SUP,PP3
Mayo Clinic Laboratories, Mayo Clinic	RCV003311702	SCV005414179	pathogenic	not provided	2024-02-05	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3_strong, PS4
Fulgent Genetics, Fulgent Genetics	RCV000169133	SCV005636143	pathogenic	Wilson disease	2024-02-20	criteria provided, single submitter	clinical testing
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