ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2131G>A (p.Gly711Arg) (rs1394999756)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586389 SCV000694415 pathogenic Wilson disease 2017-08-23 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.2131G>A (p.Gly711Arg) variant involves the alteration of a conserved nucleotide, resulting in a missense change that lies within the TM2 domain. 5/5 in silico tools predict damaging outcome for this variant. This variant is absent in 120460 control chromosomes tested in ExAC and control cohorts reported in the literature. The variant has been identified in several patients in the literature, including as a patient who carried this variant in homozygous state. Computational structure modeling predicts that the variant disrupts the protein structure, and an overlapping variant (G711D) causes copper accumulation in the liver as well as a slight increase of copper in the brain from a mouse model study. Additionally, the codon may be a mutational hotspot since G711E and G711W, in addition to the variant of interest, are among the disease variants listed in HGMD. Taken together, this variant is classified as pathogenic.
Invitae RCV000586389 SCV001575735 likely pathogenic Wilson disease 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 711 of the ATP7B protein (p.Gly711Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Wilson disease (PMID: 10544227, 16423615, 8931691). ClinVar contains an entry for this variant (Variation ID: 495405). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Gly711 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10502777, 31059521). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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