Submissions for variant NM_000053.4(ATP7B):c.2336G>A (p.Trp779Ter)

gnomAD frequency: 0.00009  dbSNP: rs137853283

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724020	SCV000232469	pathogenic	not provided	2014-06-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000144368	SCV000602611	pathogenic	Wilson disease	2022-03-08	criteria provided, single submitter	clinical testing	The ATP7B c.2336G>A; p.Trp779Ter variant (rs137853283) is reported in the literature as one of the most common variants in a Wilson disease cohort study (Vrabelova 2005), and has been described in at least one individual who was homozygous for the variant (Waldenstrom 1996). This variant is also reported in ClinVar (Variation ID: 156284), and is found in the general population with an overall allele frequency of 0.0039% (11/280818 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Vrabelova S et al. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol Genet Metab. 2005 Sep-Oct;86(1-2):277-85. PMID: 15967699. Waldenstrom E et al. Efficient detection of mutations in Wilson disease by manifold sequencing. Genomics. 1996 Nov 1;37(3):303-9. PMID: 8938442.
Invitae	RCV000144368	SCV000813134	pathogenic	Wilson disease	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp779*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Wilson disease (PMID: 8938442, 23982005; Invitae). ClinVar contains an entry for this variant (Variation ID: 156284). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000724020	SCV000890230	pathogenic	not provided	2021-11-09	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 26207595, 21610751, 28856630, 8938442, 28753182, 30230192, 31144528, 30965071, 23982005, 11690702, 15967699, 15202786)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000144368	SCV000916619	pathogenic	Wilson disease	2017-11-22	criteria provided, single submitter	clinical testing	Variant summary: The ATP7B c.2336G>A (p.Trp779X) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 8/246088 control chromosomes (gnomAD) at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). Multiple compound heterozygote and homozygote WD pts have been reported via publications (Vrabelova_2005, Moller_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV000144368	SCV001525668	pathogenic	Wilson disease	2018-08-13	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000144368	SCV001977323	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000724020	SCV002525823	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing	PP5, PM2, PS4, PVS1
Ambry Genetics	RCV002453462	SCV002737672	pathogenic	Inborn genetic diseases	2017-06-14	criteria provided, single submitter	clinical testing	The p.W779* pathogenic mutation (also known as c.2336G>A), located in coding exon 8 of the ATP7B gene, results from a G to A substitution at nucleotide position 2336. This changes the amino acid from a tryptophan to a stop codon within coding exon 8. This mutation was detected in one homozygous individual with a clinical diagnosis of Wilson disease, who presented at age 18 with moderate neurologic disease (Waldenström E et al. Genomics, 1996 Nov;37:303-9). In two cohorts of individuals with Wilson disease, this mutation was found in greater than 10 alleles; however, complete genotype information was not provided (Gromadzka G et al. Clin. Genet., 2005 Dec;68:524-32; Vrabelova S et al. Mol. Genet. Metab. Jun;86:277-85). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
CeGaT Center for Human Genetics Tuebingen	RCV000724020	SCV003917290	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	ATP7B: PVS1, PM2, PP4
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000144368	SCV000189435	not provided	Wilson disease		no assertion provided	not provided
Natera, Inc.	RCV000144368	SCV001459728	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing