Submissions for variant NM_000053.4(ATP7B):c.4301C>T (p.Thr1434Met)

gnomAD frequency: 0.00282  dbSNP: rs60986317

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000251030	SCV000052027	likely benign	not specified	2022-03-03	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.4301C>T (p.Thr1434Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 249530 control chromosomes, including 1 homozygote, in the gnomAD database (v 2.1 exomes dataset). The variant was observed predominantly within the African or African-American subpopulation at a frequency of 0.0053. This frequency is close to the maximum expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0053 vs. 0.0054), suggesting that the variant might be benign. The variant, c.4301C>T, has been reported in the literature in individuals affected with Wilson Disease (Loudianos_1999, Abdelghaffar_2008, Lepori_2012) and other disease phenotypes (e.g. Vasta_2012, Demily_2017, Coutelier_2018). However, co-occurrences with other pathogenic variant have been reported (ATP7B homozygous c.3809A>G (p.Asn1270Ser); Abdelghaffar_2008) that could explain the patient's phenotype, thus providing supporting evidence for a benign role. A recent study found the variant in French residents, who were treated with indications other than Wilson Disease (WD), hepatic or neurological diseases, at a frequency of 0.00645 (i.e. 9/1394 alleles), whereas the variant was not found in their WD database, which included 496 index cases. Publications also reported experimental evidence evaluating an impact on protein function, and showed no damaging effect for this variant (Braiterman_2011, Hsi_2003). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=8) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224611	SCV000280605	uncertain significance	not provided	2015-02-06	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV000251030	SCV000301725	benign	not specified		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029379	SCV000626863	likely benign	Wilson disease	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000029379	SCV001139345	uncertain significance	Wilson disease	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224611	SCV001156173	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	ATP7B: BP4, BS2
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000029379	SCV001368969	uncertain significance	Wilson disease	2018-11-26	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PM5.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000029379	SCV001473530	likely benign	Wilson disease	2023-06-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000029379	SCV001653486	uncertain significance	Wilson disease	2021-05-18	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000224611	SCV001713623	uncertain significance	not provided	2019-07-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000029379	SCV002060307	uncertain significance	Wilson disease	2021-10-01	criteria provided, single submitter	clinical testing	NM_000053.3(ATP7B):c.4301C>T(T1434M) is a missense variant classified as a variant of uncertain significance in the context of Wilson disease. T1434M has been observed in cases with relevant disease (PMID 29482223, 18483695, 10544227, 22484412, 32154060). Functional assessments of this variant are available in the literature (PMID: 14962673, 21454443). T1434M has been observed in population frequency databases (gnomAD: ASJ 0.91%). In summary, there is insufficient evidence to classify NM_000053.3(ATP7B):c.4301C>T(T1434M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	RCV000029379	SCV002522184	uncertain significance	Wilson disease	2021-08-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000029379	SCV004361951	likely benign	Wilson disease	2018-03-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000251030	SCV004848119	likely benign	not specified	2019-04-18	criteria provided, single submitter	clinical testing	The p.Thr1323Met variant in ATP7B (also described as p.Thr1434Met) has been reported in at least 1 heterozygous individual and 1 homozygous individual with Wilson disease; however the homozygous individual was also homozygous for a known pathogenic variant in ATP7B (Loudianos 1999, Abdel Ghaffar 2008, Abdel Ghaffar 2011). This variant has also been reported in ClinVar (Variation ID#35730). This variant was also reported in 4 heterozygous individuals with other neuropsychiatric diseases and were not observed to have typical Wilson disease features (Bell 2011 and Demily 2017). In vitro functional studies in yeast do not suggest copper transport or complementation are impaired (Hsi 2004); however, these types of assays may not accurately represent biological function. This variant has been identified in 0.877% (89/10150) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs60986317). In summary, due to its population frequency and functional data and findings with other pathogenic variants, the p.Thr1323Met variant is classified as likely benign. ACMG/AMP Criteria applied: BS3, BP4 (Richards 2015).
Natera, Inc.	RCV000029379	SCV001454144	benign	Wilson disease	2020-04-15	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000224611	SCV001744039	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000224611	SCV001808381	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000224611	SCV001931768	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224611	SCV001974403	likely benign	not provided		no assertion criteria provided	clinical testing