Submissions for variant NM_000053.4(ATP7B):c.1728G>A (p.Ala576=)

gnomAD frequency: 0.00442  dbSNP: rs116703544

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000422745	SCV000527541	benign	not specified	2016-09-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587027	SCV000694404	benign	not provided	2016-10-27	criteria provided, single submitter	clinical testing	Variant summary: The ATP7B c.1728G>A (p.Ala576Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 186/122606 control chromosomes (3 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0161224 (158/9800). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). In addition, three homozygotes were found in the African subpopulation in controls. These data suggest the variant of interest is a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Based on the splicing prediction and allele frequency in controls, this variant is classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079657	SCV000752262	benign	Wilson disease	2025-01-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001079657	SCV001268681	likely benign	Wilson disease	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001079657	SCV002048091	benign	Wilson disease	2023-02-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002402169	SCV002713711	benign	Inborn genetic diseases	2017-08-10	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV001079657	SCV002799197	benign	Wilson disease	2021-09-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587027	SCV004133158	likely benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	ATP7B: BP4, BP7, BS1
All of Us Research Program, National Institutes of Health	RCV001079657	SCV004846332	benign	Wilson disease	2024-02-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000587027	SCV005215659	likely benign	not provided		criteria provided, single submitter	not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000587027	SCV001807186	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000422745	SCV001976066	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003932639	SCV004749360	benign	ATP7B-related disorder	2019-04-05	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).