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

dbSNP: rs1394999756

Total submissions: 4

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	2020-12-21	criteria provided, single submitter	clinical testing	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. 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.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. 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 has been observed in individual(s) with Wilson disease (PMID: 10544227, 16423615, 8931691). ClinVar contains an entry for this variant (Variation ID: 495405). This variant is not present in population databases (ExAC no frequency). 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.
Genome-Nilou Lab	RCV000586389	SCV001977347	likely pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003326468	SCV004033263	likely pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	ATP7B: PM2, PM5, PP4:Moderate, PM3:Supporting, PP3