ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2072G>T (p.Gly691Val) (rs1555291801)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671031 SCV000795969 likely pathogenic Wilson disease 2017-11-26 criteria provided, single submitter clinical testing
Invitae RCV000671031 SCV000825523 pathogenic Wilson disease 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 691 of the ATP7B protein (p.Gly691Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous or in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 25497208). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Gly691Arg) has been determined to be likely pathogenic (PMID: 17718866, 23389864, 9671269). This suggests that the glycine residue is critical for ATP7B protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
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.

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