Submissions for variant NM_000053.4(ATP7B):c.813C>A (p.Cys271Ter)

dbSNP: rs572147914

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169298	SCV000220617	pathogenic	Wilson disease	2014-08-20	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000724151	SCV000700720	pathogenic	not provided	2016-10-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169298	SCV000916631	pathogenic	Wilson disease	2018-05-14	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.813C>A (p.Cys271X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 9.4e-05 in 244686 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (9.4e-05 vs 5.40e-03), allowing no conclusion about variant significance. The variant, c.813C>A, has been reported in the literature in multiple individuals affected with Wilson Disease (Mukherjee_2014, Coffey_2013, Duc_1998). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169298	SCV001591098	pathogenic	Wilson disease	2025-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys271*) 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 (rs572147914, gnomAD 0.07%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 21034864, 30426382, 31059521). ClinVar contains an entry for this variant (Variation ID: 188930). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000724151	SCV001713638	pathogenic	not provided	2024-08-12	criteria provided, single submitter	clinical testing	PP1, PM2_moderate, PVS1
Suma Genomics	RCV000169298	SCV001847676	pathogenic	Wilson disease		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169298	SCV001977395	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000169298	SCV002022028	pathogenic	Wilson disease	2022-05-31	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001823123	SCV002073257	pathogenic	Intellectual disability, Wolff type		criteria provided, single submitter	clinical testing	The stop gained p.C271Ter in ATP7B (NM_000053.3) has been previously reported in multiple patients affected with Wilson disease (Aggarwal A et al, 2013; Mukherjee S et al, 2014). It has been reported in the ClinVar database as Pathogenic. The p.C271Ter variant is observed in 2/978 (0.2045%) alleles from individuals of South Asian background in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.
Arcensus	RCV000169298	SCV002564599	pathogenic	Wilson disease	2013-02-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169298	SCV002811691	pathogenic	Wilson disease	2024-04-17	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000169298	SCV004101479	pathogenic	Wilson disease		criteria provided, single submitter	clinical testing	The observed stop gained variant c.813C>A(p.Cys271Ter) in the ATP7B gene has been reported previously in multiple individuals affected with Wilson disease. It is the most prevalent mutation with an allele frequency of 16%, 10%, and 20.2% in eastern, southern, and western Indian populations respectively (Singh N, et al., 2019; Aggarwal A, et al., 2013). This variant is reported with the allele frequency 0.01% in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic by multiple submitters. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169298	SCV004216270	pathogenic	Wilson disease	2024-03-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000169298	SCV004814485	pathogenic	Wilson disease	2024-04-25	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 2 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 reported in the compound heterozygous and homozygous states in many individuals affected with Wilson disease and is one of the most common mutations in India associated with Wilson disease (PMID: 9887381, 16133174, 17264425, 21034864, 21645214, 23518715, 23551039, 24094725, 30426382, 31059521). This variant has been identified in 24/247982 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	RCV000169298	SCV004848328	pathogenic	Wilson disease	2020-06-11	criteria provided, single submitter	clinical testing	The p.Cys271X variant in ATP7B has been previously reported in many homozygous and compound heterozygous individuals with Wilson disease, and segregated with disease in at least two affected relatives (Aggarwal 2013, Coffey 2013, Duc 1998, Gupta 2005, Khan 2018, Lee 2011, Mukerjee 2014, Santhosh 2006). The majority of these individuals were from the Indian subcontinent. This variant has also been identified in 0.07% (23/30584) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 271, 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.
GeneDx	RCV000724151	SCV005201660	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Most common pathogenic variant identified in individuals with Wilson disease in India (PMID: 31059521, 24094725); 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: 31589614, 25525159, 30426382, 34643937, 35342245, 9887381, 24094725, 23551039, 23518715, 31059521)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000169298	SCV005687694	pathogenic	Wilson disease	2025-02-03	criteria provided, single submitter	clinical testing
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000169298	SCV005873781	likely pathogenic	Wilson disease	2021-10-02	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169298	SCV001453797	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000724151	SCV001740988	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000724151	SCV001806932	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000724151	SCV001928350	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751316	SCV005363945	pathogenic	ATP7B-related disorder	2024-03-24	no assertion criteria provided	clinical testing	The ATP7B c.813C>A variant is predicted to result in premature protein termination (p.Cys271*). This variant has been detected in the homozygous and compound heterozygous state in a large number of individuals with Wilson disease, particularly of East Indian descent (Duc et al. 1998. PubMed ID: 9887381; Mukherjee et al. 2014. PubMed ID: 24094725). It is listed as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/188930/). This variant is reported in 0.075% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in ATP7B are expected to be pathogenic. This variant is interpreted as pathogenic.