Submissions for variant NM_000053.4(ATP7B):c.3784G>T (p.Val1262Phe)

gnomAD frequency: 0.00001  dbSNP: rs769484789

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665788	SCV000789962	likely pathogenic	Wilson disease	2017-03-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665788	SCV001235665	pathogenic	Wilson disease	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1262 of the ATP7B protein (p.Val1262Phe). This variant is present in population databases (rs769484789, gnomAD 0.003%). This missense change has been observed in individual(s) with Wilson's disease (PMID: 10544227, 20485189; Invitae). 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: 550902). 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: 19937698). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000665788	SCV001977234	likely pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000665788	SCV004216466	pathogenic	Wilson disease	2024-03-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000665788	SCV004836117	pathogenic	Wilson disease	2023-11-28	criteria provided, single submitter	clinical testing	This variant was detected in multiple affected individuals as homozygous or as compound heterozygous (in trans) with a pathogenic variant, which is consistent with autosomal recessive inheritance (PMID: 10544227, 20485189, 20958917, 29930488, 35388883). It is rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant has a deleterious effect on the protein (PMID: 19937698, 35388883).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000665788	SCV004848560	likely pathogenic	Wilson disease	2022-08-26	criteria provided, single submitter	clinical testing	The p.Val1262Phe variant in ATP7B has been reported in at least 4 individuals with Wilson disease and segregated with disease in 1 affected individual from 1 family (Loudianos 1999 PMID: 10544227, Shim 2018 PMID: 29930488, Song 2022 PMID: 35388883). It has also been identified in 0.001% (1/68052) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 550902). 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 vitro functional studies provide some evidence that this variant reduces ATP7B protein expression (van den Berghe 2009 PMID: 19937698); however, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PM3, PM2_Supporting, PP1, PP3, PS3_Supporting.
Natera, Inc.	RCV000665788	SCV002086795	pathogenic	Wilson disease	2020-11-18	no assertion criteria provided	clinical testing