Submissions for variant NM_000053.4(ATP7B):c.2009_2015del (p.Ile669_Tyr670insTer)

dbSNP: rs779904655

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169214	SCV000694412	pathogenic	Wilson disease	2017-02-03	criteria provided, single submitter	clinical testing	Variant summary: The ATP7B c.2009_2015delATATGCT (p.Tyr670Terfs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.3402delC, p.Ala1135fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/120512 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant has been reported in affected individuals in the literature in both the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000169214	SCV001159414	pathogenic	Wilson disease	2022-12-23	criteria provided, single submitter	clinical testing	The ATP7B c.2009_2015del; p.Tyr670Ter variant (rs779904655), also known as 1950-1956 deletion, has been described in individuals and families affected with Wilson disease (Bull 1993, Thomas 1995). The variant is reported in ClinVar (Variation ID: 188862), and is observed in the general population at an overall frequency of 0.0024% (6/249204 alleles) in the Genome Aggregation Database. This variant deletes seven nucleotides resulting in an immediate stop codon, so it 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 Bull PC et al. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993 Dec;5(4):327-37. PMID: 8298639. Thomas GR et al. Wilson disease in Iceland: a clinical and genetic study. Am J Hum Genet. 1995 May;56(5):1140-6. PMID: 7726170.
Invitae	RCV000169214	SCV001215891	pathogenic	Wilson disease	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr670*) 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 (rs779904655, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 7726170). It has also been observed to segregate with disease in related individuals. This variant is also known as 2010del7. ClinVar contains an entry for this variant (Variation ID: 188862). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000169214	SCV002021994	pathogenic	Wilson disease	2022-12-20	criteria provided, single submitter	clinical testing
GeneDx	RCV002274945	SCV002562346	pathogenic	not provided	2022-08-09	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 (gnomAD); This variant is associated with the following publications: (PMID: 7726170, 8298639, 10502777)
CeGaT Center for Human Genetics Tuebingen	RCV002274945	SCV004033264	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	ATP7B: PVS1, PP1:Strong, PM2, PM3
Baylor Genetics	RCV000169214	SCV004216331	pathogenic	Wilson disease	2023-09-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000169214	SCV004362488	pathogenic	Wilson disease	2023-02-15	criteria provided, single submitter	clinical testing	This variant deletes 7 nucleotides in exon 7 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 1950-1956 deletion, 2010del7, or 2007del7 in the literature. This variant has been observed in the homozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 8298639, 7726170, 10502777), indicating that this variant contributes to disease. This variant has been identified in 6/249204 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.
OMIM	RCV000169214	SCV000024213	pathogenic	Wilson disease	1995-05-01	no assertion criteria provided	literature only
Counsyl	RCV000169214	SCV000220473	pathogenic	Wilson disease	2018-02-23	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169214	SCV002087856	pathogenic	Wilson disease	2020-08-27	no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV000169214	SCV004022110	pathogenic	Wilson disease	2023-07-21	no assertion criteria provided	research	The variant NM_000053.4:c.2009_2015del (chr13:51960253) in ATP7B was detected in 619 heterozygotes and 4 homozygotes out of 58K WGS Icelanders (MAF= 0,541%). Following imputation in a set of 166K Icelanders (1,782 imputed heterozygotes and 7 imputed homozygotes) we observed an association with disorders of copper metabolism (ICD10 code: E830) under a recessive model using 26 cases and 302580 controls (OR= 244.2, P= 1.9e-18). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic.