Submissions for variant NM_000053.4(ATP7B):c.525dup (p.Val176fs)

dbSNP: rs558037268

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411870	SCV000694468	pathogenic	Wilson disease	2016-10-06	criteria provided, single submitter	clinical testing	Variant summary: The ATP7B c.525dupA (p.Val176Serfs) 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. One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/120674 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant has been reported in the literature in numerous affected individuals, mainly of Chinese ancestry. Taken together, this variant is classified as pathogenic.
Invitae	RCV000411870	SCV000961685	pathogenic	Wilson disease	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val176Serfs*28) 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 (rs758115611, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with Wilson disease (PMID: 21034864, 26483271, 27022412, 29321352). This variant is also known as c.525_526insA. ClinVar contains an entry for this variant (Variation ID: 370306). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000411870	SCV001977400	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV002254294	SCV002525831	pathogenic	not provided	2022-10-31	criteria provided, single submitter	clinical testing	PM2, PVS1
Baylor Genetics	RCV000411870	SCV004216294	pathogenic	Wilson disease	2023-10-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000411870	SCV004562423	pathogenic	Wilson disease	2023-08-09	criteria provided, single submitter	clinical testing	The ATP7B c.525dup; p.Val176SerfsTer28 variant (rs558037268) is reported in the literature in multiple individuals affected with Wilson disease (Dong 2016, Panichareon 2011, Tsai 2011, Xiao 2021). This variant is also reported in ClinVar (Variation ID: 370306) and is found in the East Asian population with an overall allele frequency of 0.022% (4/17972 alleles) in the Genome Aggregation Database. This variant causes a frameshift by inserting a single nucleotide, 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: Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. PMID: 27022412. Panichareon B et al. Six novel ATP7B mutations in Thai patients with Wilson disease. Eur J Med Genet. 2011 Mar-Apr;54(2):103-7. PMID: 21034864. Tsai CH et al. Mutation analysis of Wilson disease in Taiwan and description of six new mutations. Hum Mutat. 1998;12(6):370-6. PMID: 9829905. Xiao Z et al. Molecular analysis of 53 Chinese families with Wilson's disease: Six novel mutations identified. Mol Genet Genomic Med. 2021 Sep;9(9):e1735. PMID: 34324271.
Counsyl	RCV000411870	SCV000485576	pathogenic	Wilson disease	2016-09-09	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000411870	SCV001453798	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing