ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2128G>A (p.Gly710Ser) (rs137853285)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000144365 SCV000192320 pathogenic Wilson disease 2013-12-20 criteria provided, single submitter clinical testing
GeneDx RCV000497757 SCV000589555 pathogenic not provided 2018-05-21 criteria provided, single submitter clinical testing The G710S variant in the ATP7B gene has been reported previously in the homozygous and compound heterozygous states in patients with Wilson disease (Waldenstrom et al., 1996; Battisti et al., 1999; Hua et al., 2016). The G710S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G710S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies of the G710S variant indicate that this variant leads to significantly decreased copper intake (Huster et al., 2012). Missense variants at the same residue (G710A, G710V) have been reported in individuals with Wilson disease (Ha-Hao et al., 1998; Cox et al., 2005) We interpret G710S as a pathogenic variant.
Invitae RCV000144365 SCV000626836 pathogenic Wilson disease 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 710 of the ATP7B protein (p.Gly710Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in multiple individuals affected with Wilson disease in the homozygous and in the compound heterozygous state (PMID: 27398169, 8938442, 16233999, 16133174, 10544227, 17433323, 15967699). ClinVar contains an entry for this variant (Variation ID: 156281). Experimental studies have shown that this missense change causes a copper transport deficiency (PMID: 22240481). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000144365 SCV000694414 pathogenic Wilson disease 2016-06-23 criteria provided, single submitter clinical testing Variant summary: The c.2128G>A (p.Gly710Ser) in ATP7B gene is a missense change that is located in a loop 2-3 of the A-domain; it involves a highly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. These predictions were confirmed by results of functional studies. The variant is absent from the control population dataset of ExAC. The variant was identified in multiple affected individuals (homozygotes or compound heterozygotes) presented with a classic symptoms of a WD (lowered plasma ceruloplasmin, free serum and urinary copper concentration, and the occurrence of KayserFleischer ringscharacteristic copper deposition in the corneal periphery). The variant of interest has been reported as Pathogenic by reputable database/clinical laboratory. Taking together, the variant was classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000497757 SCV000702263 pathogenic not provided 2016-10-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000144365 SCV001159106 pathogenic Wilson disease 2019-05-06 criteria provided, single submitter clinical testing The ATP7B c.2128G>A; p.Gly710Ser variant (rs137853285) has been reported in multiple individuals with Wilson disease, either homozygously or compound heterozygously (Hofer 2012, Hua 2016, Li 2011, Shah 1997, Waldenstrom 1996). Additionally, functional analysis has shown the variant protein to have decreased copper uptake and transport (Huster 2012). This variant is reported in ClinVar (Variation ID: 156281), and observed in the general population with a low overall frequency of 0.002% (4/248838 alleles) in the Genome Aggregation Database. The glycine at codon 710 is highly conserved, and computational algorithms (SIFT, PolyPhen-2) predict this variant to be damaging to the protein. Based on the above information, this variant is considered pathogenic. REFERENCES Hofer H et al. Identification of a novel Wilson disease gene mutation frequent in Upper Austria: a genetic and clinical study. J Hum Genet. 2012 Sep;57(9):564-7. Hua R et al. Mutational analysis of ATP7B in Chinese Wilson disease patients. Am J Transl Res. 2016 Jun 15;8(6):2851-61. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. Li XH et al. Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations. BMC Med Genet. 2011 Jan 11;12:6. Shah AB et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997 Aug;61(2):317-28. Waldenstrom E et al. Efficient detection of mutations in Wilson disease by manifold sequencing. Genomics. 1996 Nov 1;37(3):303-9.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000497757 SCV001248427 pathogenic not provided 2019-01-01 criteria provided, single submitter clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000144365 SCV000189432 not provided Wilson disease no assertion provided not provided
Counsyl RCV000144365 SCV001132341 pathogenic Wilson disease 2016-11-30 no assertion criteria provided clinical testing

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