Submissions for variant NM_000053.4(ATP7B):c.3886G>A (p.Asp1296Asn)

gnomAD frequency: 0.00014  dbSNP: rs199821556

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000148375	SCV000267216	likely pathogenic	Wilson disease	2016-03-18	criteria provided, single submitter	reference population
Counsyl	RCV000148375	SCV000800564	uncertain significance	Wilson disease	2017-07-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000148375	SCV000915632	uncertain significance	Wilson disease	2018-10-18	criteria provided, single submitter	clinical testing	The ATP7B c.3886G>A (p.Asp1296Asn) variant is a missense variant that has been reported in at least two studies and is found in a compound heterozygous state in three individuals from two families, including two brothers, with presymptomatic Wilson disease (Ohya et al. 2002; Nakayama et al. 2008). In each family an unaffected parent was heterozygous for the p.Asp1296Asn variant. This variant was reported in one of 50 controls and is reported at a frequency of 0.001815 in the European (Finnish) population of the Exome Aggregation Consortium (Lin et al. 2010). The evidence for this variant is limited. The p.Asp1296Asn variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148375	SCV001411835	pathogenic	Wilson disease	2024-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1296 of the ATP7B protein (p.Asp1296Asn). This variant is present in population databases (rs199821556, gnomAD 0.2%). This missense change has been observed in individual(s) with Wilson disease (PMID: 11954751, 12032531, 18424137, 21707886, 32618023). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 161207). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATP7B protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000148375	SCV001977532	uncertain significance	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV001091634	SCV001985438	uncertain significance	not provided	2020-02-26	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21707886, 20465995, 30956230, 32248359, 25637381, 22692182, 12032531, 18424137, 11954751, 30275481)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000148375	SCV002500398	likely pathogenic	Wilson disease	2023-08-03	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3886G>A (p.Asp1296Asn) results in a conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 249436 control chromosomes (i.e. 50 / 249436 alleles) in the gnomAD database. This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATP7B causing Wilson Disease (0.0054), allowing no conclusion about variant significance. c.3886G>A has been reported in the literature in multiple individuals affected with Wilson Disease, including at least three homozygotes (Knuutinen_2021, Sipila_2020) and several compound heterozygous patients diagnosed in the presymptomatic stage (e.g. Ohya_2002, Owada_2002, Nakayama_2008, Lee_2011). 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. Six other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001091634	SCV004026260	likely pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing	PP3_STR, PM3_STR
Baylor Genetics	RCV000148375	SCV004216282	likely pathogenic	Wilson disease	2024-03-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001091634	SCV004226642	likely pathogenic	not provided	2022-02-23	criteria provided, single submitter	clinical testing	PP1, PP3, PP4, PM2, PM3, PS4_moderate
All of Us Research Program, National Institutes of Health	RCV000148375	SCV004844580	uncertain significance	Wilson disease	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 1296 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in the homozygous state in individuals affected with Wilson disease (PMID: 32618023, 33948933) and in the compound heterozygous state in individuals presymptomatic for Wilson disease (PMID: 11954751, 12032531, 18424137). This variant has been detected in an individual with cancer (PMID: 20045993) and in unaffected populations (PMID: 20465995, 21707886, 33260258). This variant has been identified in 56/280818 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000148375	SCV005636620	likely pathogenic	Wilson disease	2024-04-11	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148375	SCV000190072	uncertain significance	Wilson disease	2014-06-01	no assertion criteria provided	research