ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3295G>A (p.Gly1099Ser)

gnomAD frequency: 0.00001  dbSNP: rs761632029
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410034 SCV000486230 likely pathogenic Wilson disease 2016-09-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000410034 SCV001158499 likely pathogenic Wilson disease 2019-05-21 criteria provided, single submitter clinical testing The ATP7B c.3295G>A; p.Gly1099Ser variant (rs761632029) is reported in the literature in the trans-heterozygous state in multiple individuals affected with Wilson disease (Bruha 2011, Dufernez 2013, Lepori 2007, Margarit 2005, Merle 2010, Weitzman 2014). This variant is reported in ClinVar (Variation ID: 370820), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 1099 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 likely pathogenic. References: Bruha R et al. Long-term follow-up of Wilson disease: natural history, treatment, mutations analysis and phenotypic correlation. Liver Int. 2011 Jan;31(1):83-91. Dufernez F et al. Wilson disease in offspring of affected patients: report of four French families. Clin Res Hepatol Gastroenterol. 2013 Jun;37(3):240-5. Lepori MB et al. Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin. Genet Test. 2007 Fall;11(3):328-32. Margarit E et al. Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet. 2005 Jul;68(1):61-8. Merle U et al. Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease. BMC Gastroenterol. 2010 Jan 18;10:8. Weitzman E et al. Late onset fulminant Wilson's disease: a case report and review of the literature. World J Gastroenterol. 2014 Dec 14;20(46):17656-60.
Labcorp Genetics (formerly Invitae), Labcorp RCV000410034 SCV001574424 pathogenic Wilson disease 2023-10-26 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1099 of the ATP7B protein (p.Gly1099Ser). This variant is present in population databases (rs761632029, gnomAD 0.002%). This missense change has been observed in individual(s) with Wilson disease (PMID: 15952988, 23567103, 25516681). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 370820). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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 RCV000410034 SCV002766207 pathogenic Wilson disease 2022-11-14 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3295G>A (p.Gly1099Ser) 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 8e-06 in 249584 control chromosomes. c.3295G>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Wilson Disease (example, Margarit_2005, Dufernez_2013, Garcia-Villarreal_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000410034 SCV002785091 likely pathogenic Wilson disease 2021-09-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV000410034 SCV004216334 pathogenic Wilson disease 2023-09-13 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000410034 SCV004238461 pathogenic Wilson disease 2023-07-03 criteria provided, single submitter clinical testing
Natera, Inc. RCV000410034 SCV002086820 likely pathogenic Wilson disease 2020-12-04 no assertion criteria provided clinical testing

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