ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3659C>T (p.Thr1220Met)

dbSNP: rs193922107
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Total submissions: 9
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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 RCV000029374 SCV000052022 pathogenic Wilson disease 2022-08-10 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3659C>T (p.Thr1220Met) 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 249960 control chromosomes (gnomAD and Loudianos_1996, Abdelghaffar_2008). c.3659C>T has been reported in the literature in many individuals affected with Wilson Disease (e.g. Loudianos_1996, Haas_1999, Gromadzka_2005, Lepori_2007, Gojova_2008, Abdelghaffar_2008, Lovicu_2009, Moller_2011). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000029374 SCV000220459 likely pathogenic Wilson disease 2014-06-29 criteria provided, single submitter literature only
GeneDx RCV000413521 SCV000491163 pathogenic not provided 2020-09-09 criteria provided, single submitter clinical testing Published functional studies demonstrate that site-directed mutagenesis of the residues in the ATP-binding domain found that alteration of this sequence abolishes calcium transport activity (Loudianos et al. 1996); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 16283883, 17949296, 22763723, 20931554, 25497208, 24661374, 30275481, 22692182, 21610751, 23774950, 8931691, 31708252, 31400605)
Fulgent Genetics, Fulgent Genetics RCV000029374 SCV000611172 pathogenic Wilson disease 2022-05-03 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000029374 SCV000940902 pathogenic Wilson disease 2023-11-05 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1220 of the ATP7B protein (p.Thr1220Met). This variant is present in population databases (rs193922107, gnomAD 0.0009%). This missense change has been observed in individual(s) with Wilson disease (PMID: 21610751, 22763723, 24661374, 25497208; Invitae). ClinVar contains an entry for this variant (Variation ID: 35725). 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 RCV000029374 SCV001977242 likely pathogenic Wilson disease 2021-08-10 criteria provided, single submitter clinical testing
Baylor Genetics RCV000029374 SCV004216311 pathogenic Wilson disease 2024-03-24 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000029374 SCV004845316 pathogenic Wilson disease 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces threonine with methionine at codon 1220 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been observed in the compound heterozygous state in many individuals affected with autosomal recessive Wilson disease (PMID: 8931691, 10447265, 16283883, 17949296, 18371106, 18483695, 19371217, 20967755, 21610751, 22763723, 23518715, 24661374, 25497208, 34400371), indicating that this variant contributes to disease. This variant has been identified in 1/249594 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Natera, Inc. RCV000029374 SCV002086799 pathogenic Wilson disease 2021-03-12 no assertion criteria provided clinical testing

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