Submissions for variant NM_000053.4(ATP7B):c.4039G>A (p.Gly1347Ser)

gnomAD frequency: 0.00004  dbSNP: rs587783318

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145281	SCV000192358	likely pathogenic	Wilson disease	2013-02-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000145281	SCV001221182	pathogenic	Wilson disease	2023-12-31	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 1347 of the ATP7B protein (p.Gly1347Ser). This variant is present in population databases (rs587783318, gnomAD 0.08%). This missense change has been observed in individual(s) with Wilson disease (PMID: 24555712). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 157956). 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	RCV000145281	SCV001437434	likely pathogenic	Wilson disease	2024-07-31	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.4039G>A (p.Gly1347Ser) 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 0.00012 in 243552 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (0.00012 vs 0.0054), allowing no conclusion about variant significance. c.4039G>A has been reported in the literature in compound heterozygous individuals affected with Wilson Disease (Forbes_2014, Nagral_2023) with evidence of familial segregation. These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24555712, 34426522, 36112267). ClinVar contains an entry for this variant (Variation ID: 157956). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genome-Nilou Lab	RCV000145281	SCV001977531	uncertain significance	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000145281	SCV003835963	uncertain significance	Wilson disease	2022-11-22	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000145281	SCV004176655	likely pathogenic	Wilson disease	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.4039G>A (p.Gly1347Ser) variant in ATP7B gene has been reported in compound heterozygote state in individuals in at least two family members affected with Wilson Disease (Forbes N et al. 2014). It has also been observed to segregate with disease in related individuals. The p.Gly1347Ser variant has allele frequency 0.01% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic. The amino acid change p.Gly1347Ser in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 1347 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove the pathogenicity for the variant, for these reasons, this variant has been classified as Likely Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000145281	SCV004563490	likely pathogenic	Wilson disease	2023-10-13	criteria provided, single submitter	clinical testing	The ATP7B c.4039G>A; p.Gly1347Ser variant (rs587783318) is reported in the literature in the compound heterozygous state in individuals and segregates with disease in at least one family affected with Wilson disease (Forbes 2014, Nagral 2023). This variant is also reported in ClinVar (Variation ID: 157956), and is found in the general population with an overall allele frequency of 0.011% (31/274940 alleles, including a single homozygote) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.942). Based on available information, this variant is considered to be likely pathogenic. References: Forbes N et al. Evidence for synergistic effects of PRNP and ATP7B mutations in severe neuropsychiatric deterioration. BMC Med Genet. 2014 Feb 20;15:22. PMID: 24555712. Nagral A et al. Genomic Variations in ATP7B Gene in Indian Patients with Wilson Disease. Indian J Pediatr. 2023 Mar;90(3):240-248. PMID: 36112267.
All of Us Research Program, National Institutes of Health	RCV000145281	SCV004844556	uncertain significance	Wilson disease	2023-12-01	criteria provided, single submitter	clinical testing	This variant introduces an AG dinucleotide 18 bases downstream of a splice site and replaces glycine with serine at codon 1347 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). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in the compound heterozygous state in two siblings affected with autosomal recessive Wilson disease (PMID: 24555712), indicating that this variant contributes to disease. This variant has been identified in 31/274940 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Natera, Inc.	RCV000145281	SCV001455573	uncertain significance	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895025	SCV004717059	likely pathogenic	ATP7B-related disorder	2024-02-19	no assertion criteria provided	clinical testing	The ATP7B c.4039G>A variant is predicted to result in the amino acid substitution p.Gly1347Ser. This variant has been reported in the compound heterozygous state in individuals with Wilson disease (Forbes et al. 2014. PubMed ID: 24555712; Table 3, Nagral et al. 2022. PubMed ID: 36112267). One of the siblings, who was also compound heterozygous and had a classical biochemical phenotype of Wilson disease, was asymptomatic, suggesting this variant may be hypomorphic (Forbes et al. 2014. PubMed ID: 24555712). This variant is reported in 0.080% of alleles, including one homozygote, in individuals of South Asian descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic.