Submissions for variant NM_000053.4(ATP7B):c.3716T>G (p.Val1239Gly)

gnomAD frequency: 0.00001  dbSNP: rs374628199

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000541103	SCV000626858	likely pathogenic	Wilson disease	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1239 of the ATP7B protein (p.Val1239Gly). This variant is present in population databases (rs374628199, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Wilson disease (PMID: 10502777, 23518715, 34470610; Invitae). ClinVar contains an entry for this variant (Variation ID: 456557). 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%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22692182). This variant disrupts the p.Val1239 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been observed in individuals with ATP7B-related conditions (PMID: 35220961), which suggests that this may be a clinically significant amino acid residue. 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.
Counsyl	RCV000541103	SCV000791703	uncertain significance	Wilson disease	2017-05-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001507826	SCV001713635	likely pathogenic	not provided	2019-09-30	criteria provided, single submitter	clinical testing	PS3, PM2
Genome-Nilou Lab	RCV000541103	SCV001977542	uncertain significance	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002350175	SCV002619529	likely pathogenic	Inborn genetic diseases	2016-03-22	criteria provided, single submitter	clinical testing	The p.V1239G variant (also known as c.3716T>G), located in coding exon 18 of the ATP7B gene, results from a T to G substitution at nucleotide position 3716. The valine at codon 1239 is replaced by glycine, an amino acid with dissimilar properties. This variant was detected in a British patient with Wilson disease; however, a second alteration was not reported (Curtis D, Hum. Mutat. 1999 ; 14(4):304-11). Functional studies of this alteration showed low protein expression and a deleterious impact on the protein function (Luoma LM, Hum. Mutat. 2010 May; 31(5):569-77). This variant was previously reported in the SNPDatabase as rs374628199. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.01% (1/12418) total alleles studied and 0.01% (1/8380) European American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
All of Us Research Program, National Institutes of Health	RCV000541103	SCV004841132	likely pathogenic	Wilson disease	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces valine with glycine at codon 1239 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). This variant alters a conserved valine residue in the phosphorylation domain of the ATP7B protein (a.a. 1004 - 1031, 1197 - 1312), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). A functional study in yeast has shown that this variant results in the lack of ATP7B protein expression and inability to complement ccc2 deficiency (PMID: 20333758). This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 10502777, 23518715, 34470610), including at least one individual in the compound heterozygous state with a second pathogenic ATP7B variant (PMID: 23518715). This variant has been identified in 1/249548 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Natera, Inc.	RCV000541103	SCV001455583	uncertain significance	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing