Submissions for variant NM_000053.4(ATP7B):c.2978C>T (p.Thr993Met)

gnomAD frequency: 0.00006  dbSNP: rs200290721

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670460	SCV000795314	uncertain significance	Wilson disease	2017-11-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001310697	SCV001500602	uncertain significance	not provided	2020-10-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001310697	SCV001780110	uncertain significance	not provided	2020-08-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in two unrelated patients with bipolar disorder and schizophrenia (Sriretnakumar et al., 2019); This variant is associated with the following publications: (PMID: 30556376, 22692182, 23219664, 17949296, 18728530)
Genome-Nilou Lab	RCV000670460	SCV002027160	uncertain significance	Wilson disease	2021-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000670460	SCV002203554	pathogenic	Wilson disease	2024-01-18	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 993 of the ATP7B protein (p.Thr993Met). This variant is present in population databases (rs200290721, gnomAD 0.02%). This missense change has been observed in individual(s) with Wilson disease (PMID: 17949296, 23219664). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as T993W. ClinVar contains an entry for this variant (Variation ID: 554771). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469248	SCV002766290	uncertain significance	not specified	2024-08-07	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.2978C>T (p.Thr993Met) results in a non-conservative amino acid change in 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 8.5e-05 in 248286 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (8.5e-05 vs 0.0054), allowing no conclusion about variant significance. c.2978C>T has been reported in the literature as a non-informative genotype (second allele/genotype not clearly specified) reported among Wilson Disease chromosomes (example, Lepori_2007, cited in Zappu_2008, Gialluisi_2013) and as a compound heterozygous genotype in at-least one individual affected with clinically and biochemically consistent diagnosis of Wilson Disease (example, Loudianos_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23486543, 17949296, 23219664, 18728530). ClinVar contains an entry for this variant (Variation ID: 554771). Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000670460	SCV003800536	uncertain significance	Wilson disease	2022-04-15	criteria provided, single submitter	clinical testing	The ATP7B c.2978C>T; p.Thr993Met variant (rs200290721) is reported in the literature in two individuals affected with Wilson disease, in one case on the opposite chromosome to a second pathogenic variant (Lepori 2007, Loudianos 2013). This variant is reported in ClinVar (Variation ID: 554771) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The threonine at codon 993 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.865). Due to limited information, the clinical significance of the p.Thr993Met variant is uncertain at this time. References: Lepori et al. Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin. Genet Test. 2007 Fall;11(3):328-32. PMID: 17949296. Loudianos G et al. Wilson's disease in two consecutive generations: the detection of three mutated alleles in the ATP7B gene in two Sardinian families. Dig Liver Dis. 2013 Apr;45(4):342-5. PMID: 23219664.
Mayo Clinic Laboratories, Mayo Clinic	RCV001310697	SCV004226662	likely pathogenic	not provided	2022-07-26	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3
All of Us Research Program, National Institutes of Health	RCV000670460	SCV004845445	uncertain significance	Wilson disease	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 993 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Wilson disease (PMID: 17949296, 23219664). This variant has been identified in 24/279690 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004026114	SCV004913437	uncertain significance	Inborn genetic diseases	2021-05-29	criteria provided, single submitter	clinical testing	The c.2978C>T (p.T993M) alteration is located in exon 13 (coding exon 13) of the ATP7B gene. This alteration results from a C to T substitution at nucleotide position 2978, causing the threonine (T) at amino acid position 993 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000670460	SCV002086837	uncertain significance	Wilson disease	2020-03-13	no assertion criteria provided	clinical testing