Submissions for variant NM_000053.4(ATP7B):c.3955C>T (p.Arg1319Ter)

gnomAD frequency: 0.00009  dbSNP: rs193922109

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029377	SCV000052025	pathogenic	Wilson disease	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000029377	SCV000192356	pathogenic	Wilson disease	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000494120	SCV000582410	pathogenic	not provided	2021-12-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 22774841, 8938442, 11472373, 7626145, 8533760, 10544227, 19118915, 18483695, 25497208, 34240825, 25525159, 18371106, 31708252, 34324271, 23333878, 27022412, 23518715, 21796144, 21682854, 20967755, 18034201, 16283883, 31589614, 30556376, 30291343, 32513368)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000029377	SCV000602617	pathogenic	Wilson disease	2024-08-05	criteria provided, single submitter	clinical testing	The ATP7B c.3955C>T; p.Arg1319Ter variant (rs193922109) is described in the medical literature as homozygous or in combination with other pathogenic variants in individuals with Wilson disease (Abdelghaffar 2008, Balashova 2020, Deguti 2004, Margarit 2005, Waldenstrom 1996). This variant is found in the general population with an overall allele frequency of 0.007% (20/280972 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. Considering available information, this variant is classified as pathogenic. References: Abdelghaffar TY et al. Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations. J Hum Genet. 2008;53(8):681. Balashova MS et al. The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation. J Trace Elem Med Biol. 2020 May;59:126420. PMID: 31708252. Deguti MM et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 Apr;23(4):398. Margarit E et al. Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet. 2005 Jul;68(1):61-8. Waldenstrom E et al. Efficient detection of mutations in Wilson disease by manifold sequencing. Genomics. 1996 Nov 1;37(3):303-9.
Fulgent Genetics, Fulgent Genetics	RCV000029377	SCV000611175	pathogenic	Wilson disease	2017-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000029377	SCV000626862	pathogenic	Wilson disease	2025-01-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1319*) 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). This variant is present in population databases (rs193922109, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 893844, 7626145, 15024742, 15952988, 18483695, 21682854, 21796144, 23518715, 27022412). ClinVar contains an entry for this variant (Variation ID: 35728). For these reasons, this variant has been classified as Pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000029377	SCV000746793	pathogenic	Wilson disease	2017-12-18	criteria provided, single submitter	clinical testing
Institute for Genomic Medicine, Nationwide Children's Hospital	RCV000029377	SCV001571614	pathogenic	Wilson disease	2021-04-20	criteria provided, single submitter	research	The p.Arg1319* nonsense variant in ATP7B is a well-established pathogenic variant and has been reported in numerous patients to date. It is present at very low frequency in the gnomAD database (MAF<0.0001) and is predicted to truncate a significant portion of the protein. Multiple reputable laboratories have recently reported it as pathogenic. We interpret the variant as pathogenic. We identified this variant in a proband with clinical Wilson's disease; it was in compound-heterozygous state with a synonymous change (p.Leu1015=) shown to cause exon skipping by research RNA-seq. In that same experiment, we observed that the p.Arg1319* variant was present in <25% of RNA reads, suggesting that variant transcripts are subject to nonsense-mediated decay.
Mayo Clinic Laboratories, Mayo Clinic	RCV000494120	SCV001713628	pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing	PM2, PVS1
Genome-Nilou Lab	RCV000029377	SCV001977222	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000494120	SCV002063104	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371783	SCV002624018	pathogenic	Inborn genetic diseases	2015-05-01	criteria provided, single submitter	clinical testing	The p.R1319* pathogenic mutation (also known as c.3955C>T and p.R1319X), located in coding exon 19 of the ATP7B gene, results from a C to T substitution at nucleotide position 3955. This changes the amino acid from an arginine to a stop codon within coding exon 19. This mutation was identified in the homozygous state in four patients with a clinical diagnosis of Wilson disease and who exhibited lower serum copper levels (Nicastro E et al. J Hepatol. 2009;50(3):555-61). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Revvity Omics, Revvity	RCV000029377	SCV003811212	pathogenic	Wilson disease	2024-01-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000029377	SCV004216292	pathogenic	Wilson disease	2024-03-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000029377	SCV004844567	pathogenic	Wilson disease	2024-09-11	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 19 of the ATP7B gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in the compound heterozygous state or homozygous state in many individuals affected with autosomal recessive Wilson disease (PMID: 7626145, 8533760, 8938442, 9311736, 10544227, 11472373,15024742, 15952988, 16545904, 17897870, 18034201, 18371106, 18483695, 19118915, 20967755, 21682854, 21796144, 23333878, 23518715, 27022412, 31708252), indicating that this variant contributes to disease. This variant has been identified in 20/280972 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000029377	SCV004847777	pathogenic	Wilson disease	2020-06-11	criteria provided, single submitter	clinical testing	The p.Arg1319X variant in ATP7B has been previously reported in >15 probands with Wilson disease, including at least 10 compound heterozygous and three homozygous individuals, and has segregated in 4 affected family members (Coffey 2013, Abdelghaffar 2008, Deguti 2004). This variant has been identified in 0.01% (14/128714) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1319, which is predicted to lead to a truncated or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PP1_Moderate, PP4.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000029377	SCV005052027	pathogenic	Wilson disease	2024-02-01	criteria provided, single submitter	curation
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000029377	SCV005399167	pathogenic	Wilson disease	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Wilson disease (MIM#277900). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 19 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in individuals with Wilson disease and classified as pathogenic by diagnostic laboratories in ClinVar (PMID: 32513368). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Counsyl	RCV000029377	SCV000220371	pathogenic	Wilson disease	2015-07-14	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000029377	SCV001455575	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751225	SCV005344645	pathogenic	ATP7B-related disorder	2024-04-17	no assertion criteria provided	clinical testing	The ATP7B c.3955C>T variant is predicted to result in premature protein termination (p.Arg1319*). This variant has been reported to be pathogenic for Wilson disease (see for example, Thomas et al. 1995. PubMed ID: 7626145, reported as p.Arg1320*; Dong et al. 2016. PubMed ID: 27022412; Coffey et al. 2013. PubMed ID: 23518715). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in ATP7B are expected to be pathogenic. This variant is interpreted as pathogenic.