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

gnomAD frequency: 0.00001  dbSNP: rs761632029

Total submissions: 8

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	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