ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3295G>A (p.Gly1099Ser) (rs761632029)

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Total submissions: 3
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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.
Invitae RCV000410034 SCV001574424 likely pathogenic Wilson disease 2020-02-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1099 of the ATP7B protein (p.Gly1099Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs761632029, ExAC 0.001%). This variant has been observed to segregate with Wilson disease in a family (PMID: 15952988) and has also been observed in several individuals affected with Wilson disease (PMID: 23567103, 25516681, 15952988). ClinVar contains an entry for this variant (Variation ID: 370820). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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