Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000004061 | SCV000626846 | pathogenic | Wilson disease | 2024-01-13 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 919 of the ATP7B protein (p.Arg919Gly). This variant is present in population databases (rs121907993, gnomAD 0.05%). This missense change has been observed in individual(s) with Wilson disease (PMID: 12376745, 17680703, 21796144; 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: 3857). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect ATP7B function (PMID: 26032686). For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000004061 | SCV000694428 | pathogenic | Wilson disease | 2016-03-31 | criteria provided, single submitter | clinical testing | Variant Summary: The variant of interest causes a missense change involving a conserved nucleotide with 5/5 in silico programs predicting a "deleterious" effect. The variant of interest was observed in the large, broad control population of ExAC with an allele frequency of 2/119980 (1/59990), predominantly in East Asians, 2/8592 (1/4296), which does not exceed the predicted maximum expected allele frequency for a pathogenic ATP7B variant of 1/185. The variant of interest has been reported in multiple affected individuals via publications in both homozygousand compound heterozygous states. A functional study does implicate the variant to negatively affect wild type function. In addition, a reputable clinical laboratory cites the variant as "likely pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. |
Baylor Genetics | RCV000004061 | SCV001163730 | pathogenic | Wilson disease | criteria provided, single submitter | clinical testing | ||
Genome- |
RCV000004061 | SCV001977307 | pathogenic | Wilson disease | 2021-08-10 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV001818123 | SCV002064503 | pathogenic | not provided | 2020-03-09 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the ATP7B gene demonstrated a sequence change, c.2755C>G, in exon 12 that results in an amino acid change, p.Arg919Gly. This sequence change has been described in the gnomAD database with a low population frequency of 0.056% in the East Asian population (dbSNP rs121907993). This sequence change has previously been described in multiple patient with Wilson disease in both homozygous and compound heterozygous state (PMID: 21796144,17680703,12376745). The p.Arg919Gly change affects a moderately conserved amino acid residue located in a domain of the ATP7B protein that is known to be functional. The p.Arg919Gly substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These collective evidences indicate that this sequence change is pathogenic, however functional studies have not been performed to prove this conclusively. |
OMIM | RCV000004061 | SCV000024227 | pathogenic | Wilson disease | 2002-01-01 | no assertion criteria provided | literature only | |
Counsyl | RCV000004061 | SCV000220677 | pathogenic | Wilson disease | 2016-07-09 | no assertion criteria provided | clinical testing | |
Natera, |
RCV000004061 | SCV001459719 | pathogenic | Wilson disease | 2020-09-16 | no assertion criteria provided | clinical testing |