Submissions for variant NM_000053.4(ATP7B):c.3317T>A (p.Val1106Asp)

dbSNP: rs775541743

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411980	SCV000487096	likely pathogenic	Wilson disease	2016-10-11	criteria provided, single submitter	clinical testing
Invitae	RCV000411980	SCV001574423	likely pathogenic	Wilson disease	2021-10-01	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Val1106 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14966923, 26483271, 27022412, 28212618, 30702195). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ATP7B function (PMID: 18203200). 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: 371498). This missense change has been observed in individual(s) with Wilson Disease (PMID: 8938442, 20082719). This variant is present in population databases (rs775541743, ExAC 0.001%). This sequence change replaces valine with aspartic acid at codon 1106 of the ATP7B protein (p.Val1106Asp). The valine residue is moderately conserved and there is a large physicochemical difference between valine and aspartic acid.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508707	SCV001715039	likely pathogenic	not provided	2019-05-07	criteria provided, single submitter	clinical testing	PS3, PM2
All of Us Research Program, National Institutes of Health	RCV000411980	SCV004845384	uncertain significance	Wilson disease	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with aspartic acid at codon 1106 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). Functional studies performed in yeast assays have shown that this variant disrupts protein expression and copper transport (PMID: 18203200). This variant has been reported in individuals affected with Wilson disease (PMID: 8938442, 20082719). This variant has been identified in 1/249576 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.