Submissions for variant NM_000053.4(ATP7B):c.98T>C (p.Met33Thr)

gnomAD frequency: 0.00064  dbSNP: rs184868522

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000588851	SCV000227003	uncertain significance	not provided	2015-03-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000029385	SCV000384688	uncertain significance	Wilson disease	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000588851	SCV000512209	uncertain significance	not provided	2023-01-30	criteria provided, single submitter	clinical testing	Observed with a missense variant in a patient with late-onset Wilson disease, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Barros de Oliveira et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23518715, 34620762, 36632541, 24253677)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588851	SCV000694471	uncertain significance	not provided	2016-08-09	criteria provided, single submitter	clinical testing	Variant summary: The ATP7B c.98T>C (p.Met33Thr) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 73/122432 control chromosomes at a frequency of 0.0005962, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant was reported in an affected individual in the literature without strong evidence for causality. In addition, one clinical diagnostic laboratories/reputable databases has classified this variant as a VUS. Taken together, this variant is classified as VUS until additional evidence becomes available.
Ambry Genetics	RCV000624795	SCV000742290	uncertain significance	Inborn genetic diseases	2017-03-10	criteria provided, single submitter	clinical testing
Invitae	RCV000029385	SCV000938318	uncertain significance	Wilson disease	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 33 of the ATP7B protein (p.Met33Thr). This variant is present in population databases (rs184868522, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Wilson disease (PMID: 23518715). ClinVar contains an entry for this variant (Variation ID: 35736). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000588851	SCV001248432	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	ATP7B: PM2, PM3:Supporting
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000029385	SCV001473032	uncertain significance	Wilson disease	2020-08-12	criteria provided, single submitter	clinical testing	The ATP7B c.98T>C; p.Met33Thr variant (rs184868522), to our knowledge, is not reported in an individual affected with Wilson disease, but has been described in an unaffected individual (Squitti 2019). The variant is listed in the ClinVar database (Variation ID: 35736) and is reported in the general population with an overall allele frequency of 0.06% (180/280858 alleles) in the Genome Aggregation Database. The methionine at codon 33 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Met33Thr variant is uncertain at this time. References: Squitti R et al. A case of a mild Wolfram Syndrome with concomitant ATP7B mutation. CellR4. 2019; 7: e2735.
Genome-Nilou Lab	RCV000029385	SCV002027188	uncertain significance	Wilson disease	2021-09-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407365	SCV004115127	uncertain significance	ATP7B-related condition	2023-09-13	criteria provided, single submitter	clinical testing	The ATP7B c.98T>C variant is predicted to result in the amino acid substitution p.Met33Thr. This variant was previously reported in a clinically asymptomatic individual with decreased serum copper and ceruloplasmin levels but increased urinary copper after a D-penicillamine challenge test (Squitti et al. 2019. PubMed ID: 33869661). The variant was also seen in an elderly man diagnosed with late-onset Wilson disease who also carried a second ATP7B variant of uncertain significance (Barros de Oliveira Sá et al. 2022. PubMed ID: 36632541).This variant is reported in 0.11% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-52549258-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mayo Clinic Laboratories, Mayo Clinic	RCV000588851	SCV004226463	uncertain significance	not provided	2023-04-12	criteria provided, single submitter	clinical testing	PM2
Natera, Inc.	RCV000029385	SCV001460308	uncertain significance	Wilson disease	2020-04-15	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000588851	SCV001740629	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000588851	SCV001807840	likely benign	not provided		no assertion criteria provided	clinical testing