Submissions for variant NM_000053.4(ATP7B):c.778dup (p.Gln260fs)

dbSNP: rs786204570

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169312	SCV000220636	likely pathogenic	Wilson disease	2014-08-26	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169312	SCV000694470	pathogenic	Wilson disease	2017-02-14	criteria provided, single submitter	clinical testing	Variant summary: The ATP7B c.778dupC (p.Gln260Profs) 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 likely pathogenic/pathogenic by our laboratory (e.g. c.813delC (p.Cys271fs), c.845delT (p.Leu282fs), and c.1145_1151delCCCAACT (p.Ser382fs)). Mutation taster predicts a damaging outcome for this variant. This variant is absent in 120078 control chromosomes, while it was reported in multiple Wilson disease patients indicating pathogenicity. Moreover, HGMD lists several variants affecting the same codon indicating the variant to be located in a mutational hotspot and further supporting pathogenicity. One clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169312	SCV000752251	pathogenic	Wilson disease	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln260Profs*10) 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 (rs786204570, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 10980554, 11216666, 19172127, 20082719). This variant is also known as 777insC, 778insC, or 779insC. ClinVar contains an entry for this variant (Variation ID: 188938). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001560289	SCV001782669	pathogenic	not provided	2021-08-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Frameshift 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: 10980554, 19172127, 11216666, 20082719)
Genome-Nilou Lab	RCV000169312	SCV001977397	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001560289	SCV002525829	likely pathogenic	not provided	2021-11-08	criteria provided, single submitter	clinical testing	PM2, PVS1
Fulgent Genetics, Fulgent Genetics	RCV000169312	SCV002785210	pathogenic	Wilson disease	2021-09-03	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000169312	SCV004099059	likely pathogenic	Wilson disease	2023-08-23	criteria provided, single submitter	clinical testing	PVS1, PM2
Baylor Genetics	RCV000169312	SCV004216438	pathogenic	Wilson disease	2023-11-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001560289	SCV004701957	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	ATP7B: PVS1, PM3:Strong, PM2, PP4
All of Us Research Program, National Institutes of Health	RCV000169312	SCV005426834	pathogenic	Wilson disease	2024-07-29	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide in exon 2 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is also known as c.778insC and c.779insC in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with Wilson disease (PMID: 10980554, 11216666, 20082719, 23518715). Two of these individuals carried both ATP7B p.Lys175Serfs*28 and ATP7B p.Arg778Gly variants in combination with this variant (PMID: 27935710). This variant has been identified in 1/248652 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.
GenomeConnect, ClinGen	RCV000169312	SCV000986857	not provided	Wilson disease		no assertion provided	phenotyping only	Variant interpretted as pathogenic and reported on 07/25/2018 by GTR ID PerkinElmer Genetics, Inc.. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000169312	SCV002087895	pathogenic	Wilson disease	2020-09-21	no assertion criteria provided	clinical testing
Genomics And Bioinformatics Analysis Resource, Columbia University	RCV000169312	SCV004024121	pathogenic	Wilson disease		no assertion criteria provided	research