ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000505878 SCV000052008 uncertain significance not specified 2020-09-14 criteria provided, single submitter clinical testing Variant summary: ATP7B c.2972C>T (p.Thr991Met) results in a non-conservative amino acid change located in the 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 0.0012 in 250871 control chromosomes, predominantly at a frequency of 0.0024 within the Non-Finnish European subpopulation in the gnomAD database, including one homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0012 vs 0.0054), allowing no conclusion about variant significance. c.2972C>T was initially reported in the literature and subsequently cited by others in heterozygous state in individuals affected with Wilson Disease, without information on the presence of a second ATP7B variant (Lepori_2007, Cox_2005). These data indicate that the variant may be associated with disease. The variant has been reported as a homozygote in a fetus with prenatal diagnosis of arthrogryposis and a diagnosis not compatible with Wilson Disease (Drury_2015). In addition, it has also been observed 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). Most recently, a report cites this variant as among ATP7B variants with a questionable causality and/or penetrance (Wallace_2020). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a mild/intermediate deficit when assessing the ability to complement ccc2, the yeast copper-transporting orthologue of ATP7B, function under low iron conditions at 30 degree C and 37 degree C (Luoma_2010). The physiological relevance of this finding is unclear. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=6, pathogenic/likely pathogenic, n=2). Based on the evidence outlined above, the variant retained its classification as a VUS-possibly pathogenic.
GeneDx RCV000255583 SCV000321413 uncertain significance not provided 2021-09-30 criteria provided, single submitter clinical testing 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: 16088907, 30275481, 32248359, 30556376, 22692182, 33258288, 20333758, 31980526, 26275891, 31815884, 23235335, 24253677, 26206375, 31059521, 31708252, 17949296, 27528516, 23518715)
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 RCV000029361 SCV000602616 uncertain significance Wilson disease 2020-08-12 criteria provided, single submitter clinical testing The ATP7B c.2972C>T; p.Thr991Met variant (rs41292782) has been described in two patients with Wilson disease (Cox 2005), and has been implicated as having a mild effect on protein function in a model system (Luoma 2010). This variant has also been described homozygously in a prenatal sample with arthrogryposis (Drury 2015). This variant is reported in ClinVar (Variation ID: 35712) and is found in the non-Finnish European population with an overall allele frequency of 0.24% (312/128176 alleles, including 1 homozygote) in the Genome Aggregation Database. The residue is highly conserved in mammals, and computational analyses (PolyPhen2, SIFT) suggest that the p.Thr991Met variant is deleterious. However, due to limited information, the clinical significance of the p.Thr991Met variant is uncertain at this time. References: Cox DW et al. Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry. Hum Mutat. 2005 26(3):280. Drury S et al. Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities. Prenat Diagn. 2015 Oct;35(10):1010-7. Luoma LM et al. Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B. Hum Mutat. 2010 31(5):569-77.
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 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.
Mayo Clinic Laboratories, Mayo Clinic RCV000255583 SCV001715052 pathogenic not provided 2021-03-19 criteria provided, single submitter clinical testing PS3, PS4_moderate, PM2, PM3, PP4. PP4

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.