ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3532A>G (p.Thr1178Ala)

dbSNP: rs1387431334
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001232496 SCV001405058 pathogenic Wilson disease 2023-12-03 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1178 of the ATP7B protein (p.Thr1178Ala). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with Wilson disease (PMID: 18034201, 21034864, 23235335, 24094725, 31059521). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 959197). 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%. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV001232496 SCV001977248 likely pathogenic Wilson disease 2021-08-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001232496 SCV002103723 pathogenic Wilson disease 2022-02-03 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3532A>G (p.Thr1178Ala) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of 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 249588 control chromosomes (gnomAD). c.3532A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Wilson Disease (e.g. Mak_2008, Wan_2010, Singh_2019, Xiao_2021). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV003317461 SCV004021600 likely pathogenic not provided 2023-07-18 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16696937, 22692182, 30275481, 31059521, 24094725, 23235335, 18034201, 21034864, 35470480, 34400371, 35193651, 34324271)
Baylor Genetics RCV001232496 SCV004216272 pathogenic Wilson disease 2023-10-25 criteria provided, single submitter clinical testing
Natera, Inc. RCV001232496 SCV002086806 pathogenic Wilson disease 2020-07-23 no assertion criteria provided clinical testing

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