ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2972C>T (p.Thr991Met) (rs41292782)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000505878 SCV000052008 uncertain significance not specified 2019-01-15 criteria provided, single submitter clinical testing Variant summary: ATP7B c.2972C>T (p.Thr991Met) results in a non-conservative amino acid change in Transmembrane 6 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function consistent with several publications reporting computational predictions of pathogenicity (Schushan_2012, Khurana_2015, Squitti_2014). The variant allele was found at a frequency of 0.0013 in 278679 control chromosomes, predominantly at a frequency of 0.0025 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0013 vs 0.0054), allowing no conclusion about variant significance. c.2972C>T has been reported in the literature in heterozygous state in individuals affected with Wilson Disease, without information on the presence of a second ATP7B variant in any of the reports (Lepori_2007, Cox_2005). These data indicate that the variant may be associated with disease. The variant has also been reported as a homozygote in a fetus with prenatal diagnosis of arthrogryposis and as a heterozygote or unspecified zygosity in two other individuals. One affected with ataxia and normal levels of copper/cerulloplasmin (heterozygote with a non-specific genotype) and the other with schizophrenia (unspecified zygosity), (Sriretnakumar_2019, Marelli_2016, Drury_2015). Experimental evidence evaluating an impact on protein function demonstrated that the variant causes a mild/intermediate deficit (Luoma_2010). Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (4x), likely pathogenic (2x) and once as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneDx RCV000255583 SCV000321413 likely pathogenic not provided 2019-01-14 criteria provided, single submitter clinical testing The T991M variant in the ATP7B gene has been reported in association with Wilson disease (Cox et al., 2005). Functional characterization indicated the T991M variant exhibited mild to intermediate deficits in copper transport as compared to wild-type (Luoma et al., 2010). The T991M variant is observed in 311/126278 (0.24%) alleles from individuals of non-Finnish European background, and in 348/276388 (0.126%) alleles from the global data set, including one homozygous individual, in large population cohorts (Lek et al., 2016). The T991M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with Wilson disease (Stenson et al., 2014). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255583 SCV000493243 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000255583 SCV000510667 uncertain significance not provided 2016-12-12 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000505878 SCV000602616 uncertain significance not specified 2017-03-06 criteria provided, single submitter clinical testing
Invitae RCV000029361 SCV000626848 uncertain significance Wilson disease 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 991 of the ATP7B protein (p.Thr991Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs41292782, ExAC 0.2%). This variant has been reported in the heterozygous state in individuals affected with Wilson disease, although the presence of a second ATP7B variant in these individuals cannot be determined from the data (PMID: 16088907). It has also been reported in the homozygous state in a fetus with other co-morbidities (PMID: 26275891). However, at this age it is unclear whether the patient would have been affected with Wilson Disease. ClinVar contains an entry for this variant (Variation ID: 35712). One experimental study has shown that this missense change causes an intermediate deficit in a yeast growth complementation assay (PMID: 20333758). In summary, this variant is a rare missense change that has been reported in affected individuals and has been shown to have an intermediate defect in vitro. However, it has also been observed in unaffected control individuals. For these reasons, it has been classified as a Variant of Uncertain Significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255583 SCV000700471 uncertain significance not provided 2016-09-29 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000029361 SCV000782707 pathogenic Wilson disease 2017-06-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000029361 SCV001268581 uncertain significance Wilson disease 2018-07-09 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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