Submissions for variant NM_000053.4(ATP7B):c.2300C>T (p.Pro767Leu)

gnomAD frequency: 0.00003  dbSNP: rs776668666

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806274	SCV000946263	pathogenic	Wilson disease	2023-06-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro767 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29085216). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 651012). This missense change has been observed in individual(s) with Wilson disease (PMID: 25497208). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs776668666, gnomAD 0.008%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 767 of the ATP7B protein (p.Pro767Leu).
Genome-Nilou Lab	RCV000806274	SCV001977333	likely pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV002223947	SCV002502271	likely pathogenic	not provided	2022-03-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000806274	SCV004845546	likely pathogenic	Wilson disease	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 767 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 for this variant, it alters a conserved proline residue in the transmembrane domain M4 of the ATP7B protein (a.a. 764 - 784), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). This variant has been observed in the compound heterozygous state with a pathogenic variant in the same gene in an individual affected with autosomal recessive Wilson disease (PMID: 25497208), indicating that this variant contributes to disease. This variant has been identified in 3/280964 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000806274	SCV005636197	likely pathogenic	Wilson disease	2024-04-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000806274	SCV001463838	uncertain significance	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing