Submissions for variant NM_000053.4(ATP7B):c.2072G>T (p.Gly691Val)

gnomAD frequency: 0.00002  dbSNP: rs1555291801

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671031	SCV000825523	pathogenic	Wilson disease	2023-08-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 691 of the ATP7B protein (p.Gly691Val). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly691 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9671269, 17718866, 23389864). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 555245). This missense change has been observed in individual(s) with Wilson disease (PMID: 25497208). This variant is not present in population databases (gnomAD no frequency).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000671031	SCV001158498	likely pathogenic	Wilson disease	2020-05-13	criteria provided, single submitter	clinical testing	The ATP7B c.2072G>T; p.Gly691Val variant is reported in the literature in the homozygous or trans-heterozygous state in individuals affected with Wilson disease (Paradisi 2015). This variant is reported in ClinVar (Variation ID: 555245), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 691 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.2071G>A; p.Gly691Arg) has been reported in individuals with Wilson disease (Loudianos 1998). Based on available information, the p.Gly691Val variant is considered to be likely pathogenic. References: Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. Paradisi I et al. Most frequent mutation c.3402delC (p.Ala1135GlnfsX13) among Wilson disease patients in Venezuela has a wide distribution and two old origins. Eur J Med Genet. 2015 Feb;58(2):59-65.
Genome-Nilou Lab	RCV000671031	SCV001977354	likely pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000671031	SCV004216344	pathogenic	Wilson disease	2023-11-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000671031	SCV004830771	likely pathogenic	Wilson disease	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 691 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 homozygous state and the compound heterozygous state with a second pathogenic variant in individuals affected with autosomal recessive Wilson disease (PMID: 25497208), indicating that this variant contributes to disease. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.2071G>C (p.Gly691Arg) and c.2071G>A (p.Gly691Arg), are considered to be disease-causing (ClinVar Variation ID: 3866, 2180424), suggesting that glycine at this position is important for the protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV000671031	SCV002060293	uncertain significance	Wilson disease	2021-11-16	flagged submission	clinical testing	NM_000053.3(ATP7B):c.2072G>T(G691V) is a missense variant classified as a variant of uncertain significance in the context of Wilson disease. G691V has been observed in cases with relevant disease (PMID: 25497208). Functional assessments of this variant are not available in the literature. G691V has not been observed in population frequency databases. In summary, there is insufficient evidence to classify NM_000053.3(ATP7B):c.2072G>T(G691V) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.