Submissions for variant NM_000053.4(ATP7B):c.2297C>G (p.Thr766Arg)

dbSNP: rs121907997

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004065	SCV000626840	pathogenic	Wilson disease	2022-05-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 766 of the ATP7B protein (p.Thr766Arg). This variant is present in population databases (rs121907997, gnomAD 0.0009%). This missense change has been observed in individual(s) with Wilson disease (PMID: 15557537, 21956287; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3861). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site.
Genome-Nilou Lab	RCV000004065	SCV001977334	likely pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000004065	SCV004847861	likely pathogenic	Wilson disease	2020-06-11	criteria provided, single submitter	clinical testing	The p.Thr766Arg variant in ATP7B has been identified in the homozygous state in one individual with Wilson disease (Pendlebury 2004; PMID 15557537). It was also inferred that two affected individuals with Wilson disease harbored this missense variant in trans with IVS5+1G>C variant, but these individuals were deceased and it did not appear that genetic testing was performed on these individuals (Wilcox 2011 PMID 21956287). It has been reported by one submitter in ClinVar who observed this variant in a proband who was compound heterozygous for a second pathogenic ATP7B variant, and the variants segregated in an affected family member (ClinVar Variation ID 3861). This variant was identified in 1/113270 of European chromosomes by gnomAD. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM2, PM3, PP1, PP3, PP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004065	SCV005184688	pathogenic	Wilson disease	2024-05-14	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.2297C>G (p.Thr766Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249558 control chromosomes. c.2297C>G has been reported in the literature in individuals affected with Wilson Disease (Pendlebury_2004, Wilcox_2011). Additionally, another missense variant (c.2297C>T, p.thr766Met) has been classified on the pathogenic spectrum in our laboratory. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15557537, 21956287). ClinVar contains an entry for this variant (Variation ID: 3861). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000004065	SCV005636199	pathogenic	Wilson disease	2024-05-15	criteria provided, single submitter	clinical testing
OMIM	RCV000004065	SCV000024231	pathogenic	Wilson disease	2004-11-23	no assertion criteria provided	literature only