Submissions for variant NM_000053.4(ATP7B):c.2605G>A (p.Gly869Arg)

gnomAD frequency: 0.00101  dbSNP: rs191312027

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145263	SCV000192329	pathogenic	Wilson disease	2013-06-20	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000413599	SCV000337715	pathogenic	not provided	2015-12-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000413599	SCV000490419	likely pathogenic	not provided	2024-06-02	criteria provided, single submitter	clinical testing	Described as a mild variant associated with reduced penetrance as it has been observed in association with late-onset, a mild phenotype, and in asymptomatic adult twins from a single family (PMID: 11093740, 32248359, 22692182, 23219664); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11093740, 18371106, 17433323, 17949296, 27022412, 23518715, 24720933, 24094725, 27398169, 30702195, 31708252, 30097039, 32248359, 22692182, 15952988, 23219664, 9311736, 23843956, 34426522, 33159754, 33258288, 31980526, 35637795, 35470480, 35844287, 30275481, 35314707, 36253962, 34620762, 33159804, 35220961, 34405919, 30254379, 36437915, 37445923, 36910591, 34381985, 37147621, 37937776)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000145263	SCV000584069	likely pathogenic	Wilson disease	2015-02-10	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000145263	SCV000626844	pathogenic	Wilson disease	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 869 of the ATP7B protein (p.Gly869Arg). This variant is present in population databases (rs191312027, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Wilson disease (PMID: 11093740, 15952988, 23843956, 27398169, 30702195). ClinVar contains an entry for this variant (Variation ID: 157939). 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	RCV000145263	SCV000694426	pathogenic	Wilson disease	2021-06-19	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.2605G>A (p.Gly869Arg) 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 0.00069 in 252586 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00069 vs 0.0054), allowing no conclusion about variant significance. c.2605G>A has been reported in the literature in in numerous affected individuals without K-F rings in the literature, reported in late-onset patients with mild phenotype, and in some cases, in clinically asymptomatic individuals, although with abnormal biochemical findings (low plasma Cu and CP levels, elevated urinary Cu level). Therefore, this variant represents a mild mutation with a phenotypic outcome significantly dependent on a genetic background (Dong_2016, Ferenci_2007, Gu_2013, Mukherjee_2014). 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/likely pathogenic, n=7; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000623574	SCV000741467	likely pathogenic	Inborn genetic diseases	2022-10-17	criteria provided, single submitter	clinical testing	The c.2605G>A (p.G869R) alteration is located in coding exon 11 of the ATP7B gene. This alteration results from a G to A substitution at nucleotide position 2605, causing the glycine (G) at amino acid position 869 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.073% (206/280980) total alleles studied. The highest observed frequency was 0.125% (161/128724) of European (non-Finnish) alleles. This variant was detected in an individual in conjunction with p.L708P and a mild presentation with normal liver biopsy, near normal ceruloplasmin levels, elevated liver and urinary copper levels, and was diagnosed with Wilson disease at age 26 (Garcia Villarreal, 2000). This variant was in trans with p.D765G in an individual with neurologic symptoms, hepatosplenomegaly, jaundice, Kayser-Fleischer rings, and elevated urinary copper levels (Gu, 2013). In addition, several other individuals with this and a second variant presented with a hepatic phenotype (Margarit, 2005; Hua, 2016), a Parkinsonian-like phenotype (Margarit, 2005), and a mild Wilson disease phenotype (Schushan, 2012). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000145263	SCV000885048	likely pathogenic	Wilson disease	2023-11-22	criteria provided, single submitter	clinical testing	The ATP7B c.2605G>A; p.Gly869Arg variant (rs191312027) is reported in the medical literature in several individuals with a clinical diagnosis of Wilson disease, many of whom carried an additional pathogenic variant (Dong 2016, Gu 2013, Hua 2016, Huang2022, Li 2019, Loudianos 2013, Margarit 2005, Mukherjee 2014). This variant is found in the European population with an overall allele frequency of 0.13% (161/128724 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.876). Considering available information, this variant is considered to be likely pathogenic. References: Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. PMID: 27022412. Gu S et al. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. PLoS One. 2013 Jul 2;8(7):e66526. PMID: 23843956. Hua R et al. Mutational analysis of ATP7B in Chinese Wilson disease patients. Am J Transl Res. 2016 Jun 15;8(6):2851-61. PMID: 27398169. Huang C et al. Genetic studies discover novel coding and non-coding mutations in patients with Wilson's disease in China. J Clin Lab Anal. 2022 Jun;36(6):e24459. PMID: 35470480. Li X et al. Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants. Hum Mutat. 2019 May;40(5):552-565. PMID: 30702195. Loudianos G et al. Wilson's disease in two consecutive generations: the detection of three mutated alleles in the ATP7B gene in two Sardinian families. Dig Liver Dis. 2013 Apr;45(4):342-5. PMID: 23219664. 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. PMID: 15952988. Mukherjee S et al. Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation. Parkinsonism Relat Disord. 2014 Jan;20(1):75-81. PMID: 24094725.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000145263	SCV000966821	likely pathogenic	Wilson disease	2021-12-20	criteria provided, single submitter	clinical testing	The p.Gly869Arg variant in ATP7B has been reported 6 individuals with Wilson disease, all of whom were compound heterozygous (Garcia-Villarreal 2000 PMID: 11093740, Margarit 2005 PMID: 15952988, Gu 2013 PMID: 23843956, Hua 2016 PMID: 27398169, Li 2019 PMID: 30702195). This variant has also been reported in ClinVar (Variation ID#3848). This variant has also been identified in 0.125% (161/128724) of European chromosomes by Genome Aggregation Database (gnomAD, Http://gnomad.broadinstitute.org). This frequency is consistent with the known carrier frequency of Wilson disease. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly869Arg variant is likely pathogenic for Wilson disease in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3_VStrong; PP3, PP4.
Baylor Genetics	RCV000145263	SCV001163731	pathogenic	Wilson disease	2024-03-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000413599	SCV001247799	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	ATP7B: PM3:Very Strong, PM2, PS4:Moderate, PP3
Fulgent Genetics, Fulgent Genetics	RCV000145263	SCV001752695	likely pathogenic	Wilson disease	2021-06-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000145263	SCV001977156	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000145263	SCV002021996	likely pathogenic	Wilson disease	2021-09-02	criteria provided, single submitter	clinical testing
DASA	RCV000145263	SCV002061300	pathogenic	Wilson disease	2022-01-05	criteria provided, single submitter	clinical testing	The c.2605G>A;p.(Gly869Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 157939; PMID: 23843956; 15952988; 27398169; 11093740; 30702195) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (E1-E2_ATPase domain) - PM1. The variant is present at low allele frequencies population databases (rs191312027– gnomAD 0.01032%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly869Arg) was detected in trans with a pathogenic variant (PMID: 23843956; 15952988; 27398169; 11093740; 30702195) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000413599	SCV002502950	likely pathogenic	not provided	2022-03-14	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000145263	SCV002503831	pathogenic	Wilson disease	2020-11-20	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace glycine with arginine at codon 869 of the ATP7B protein (p.Gly869Arg). The glycine residue is highly conserved (100 vertebrates, UCSC), and is located in the proton ATPase domain. There is a large physicochemical difference between glycine and arginine. The variant is present in a large population cohort at a frequency of 0.07% (rs191312027, 206/280,980 alleles, 0 homozygotes in gnomAD v2.1). It has been identified compound heterozygous with other pathogenic alleles in multiple Wilson disease cases along with reduced serum ceruloplasmin and elevated urinary copper which establishes a biochemical diagnosis (PMID: 15952988, 23843956, 27398169, 30702195 - PM3_VeryStrong, PP4). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms - PP3). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP3, PP4.
Mayo Clinic Laboratories, Mayo Clinic	RCV000413599	SCV002525822	pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing	PP3, PP4_moderate, PM2, PS4_moderate
Genetics and Molecular Pathology, SA Pathology	RCV000145263	SCV002556981	likely pathogenic	Wilson disease	2021-04-15	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000145263	SCV002767135	pathogenic	Wilson disease	2020-05-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine (exon 11). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (206 Heterozygotes, 0 Homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (2 Heterozygotes, 0 Homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (PDB). (N) 0708 - Comparable variant has been reported as a VUS (LOVD). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Li, X. et al. (2019), Mukherjee, S. et al. (2014), Shah, A. B. et al. (1997), Hua, R. et al. (2016), Bowling, K. M. et al. (2017)). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Color Diagnostics, LLC DBA Color Health	RCV000145263	SCV004362483	pathogenic	Wilson disease	2023-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 869 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported, this variant alters a conserved glycine residue in the A domain of the ATP7B protein that is involved in the ATP hydrolysis (a.a. 786 - 917), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). This variant has been reported in over twenty individuals affected with autosomal recessive Wilson disease, including up to ten individuals confirmed to be compound heterozygous with a known pathogenic variant in the same gene (PMID: 9311736, 15952988, 17433323, 23219664, 23518715, 23843956, 24094725, 27022412, 27398169, 30702195, 31980526, 33159804, 33258288; Castellano et al., 2023 EASL Congress). This variant has been identified in 206/280980 chromosomes (161/128724 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. This variant is reported to show reduced penetrance and is associated with a mild phenotype in compound heterozygous individuals with Wilson disease (PMID: 32248359, 33159804; Castellano et al., 2023 EASL Congress).
All of Us Research Program, National Institutes of Health	RCV000145263	SCV004845499	pathogenic	Wilson disease	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 869 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported, this variant alters a conserved glycine residue in the A domain of the ATP7B protein that is involved in the ATP hydrolysis (a.a. 786 - 917), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). This variant has been reported in over twenty individuals affected with autosomal recessive Wilson disease, including up to ten individuals confirmed to be compound heterozygous with a known pathogenic variant in the same gene (PMID: 9311736, 15952988, 17433323, 23219664, 23518715, 23843956, 24094725, 27022412, 27398169, 30702195, 31980526, 33159804, 33258288; Castellano et al., 2023 EASL Congress). This variant has been identified in 206/280980 chromosomes (161/128724 Non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. This variant is reported to show reduced penetrance and is associated with a mild phenotype in compound heterozygous individuals with Wilson disease (PMID: 32248359, 33159804; Castellano et al., 2023 EASL Congress).
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000145263	SCV005052028	pathogenic	Wilson disease	2024-02-01	criteria provided, single submitter	curation
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000413599	SCV001797451	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000413599	SCV001929679	uncertain significance	not provided		no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000145263	SCV004041617	pathogenic	Wilson disease	2023-10-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415974	SCV004114898	pathogenic	ATP7B-related disorder	2024-09-03	no assertion criteria provided	clinical testing	The ATP7B c.2605G>A variant is predicted to result in the amino acid substitution p.Gly869Arg. This variant was reported in the compound heterozygous state in many individuals with varied features consistent with Wilson disease (Shah et al. 1997. PubMed ID: 9311736; Margarit et al. 2005. PubMed ID: 15952988; Hua et al. 2016. PubMed ID: 27398169; Gu et al. 2013. PubMed ID: 23843956; Huang et al. 2022. PubMed ID: 35470480). However, this variant is also reported in 0.16% of alleles in individuals of European (non-Finnish) descent including 3 homozygotes in gnomAD v4.0.0. This higher than expected allele frequency is consistent with this variant being a mild or possibly low penetrance variant (García-Villarreal et al. 2000. PubMed ID: 11093740; Wallace et al. 2020. PubMed ID: 32248359). For example, this variant was reported with the p.Met645Arg variant in an individual with late onset (50 years old), mild Wilson disease (Schushan et al. 2012. PubMed ID: 22692182). In summary, this variant is interpreted as pathogenic.