Submissions for variant NM_000053.4(ATP7B):c.1607T>C (p.Val536Ala) (rs138427376)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CSER _CC_NCGL, University of Washington	RCV000029352	SCV000190070	uncertain significance	Wilson disease	2014-06-01	criteria provided, single submitter	research	Low GERP score may suggest that this variant belongs in a lower pathogenicity class
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000374856	SCV000331695	benign	not specified	2016-05-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000514302	SCV000564676	likely benign	not provided	2021-06-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one homozygous individual in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25637381, 20465995, 32248359, 18373411, 23235335, 21794208, 24253677, 30097039, 23518715, 31169307)
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000514302	SCV000609818	likely benign	not provided	2017-09-06	criteria provided, single submitter	clinical testing
Invitae	RCV000029352	SCV000626830	benign	Wilson disease	2020-12-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000374856	SCV000694399	likely benign	not specified	2021-04-28	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.1607T>C (p.Val536Ala) results in a non-conservative amino acid change located in the Heavy-metal-associated domain (HMA) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 280825 control chromosomes, predominantly at a frequency of 0.011 within the Finnish subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 2-fold the estimated maximal expected allele frequency for a pathogenic variant in ATP7B causing Wilson Disease phenotype (0.0054), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. c.1607T>C has been reported in the literature in at least one individual affected with Wilson Disease (e.g. Davies_2008), as well as unaffected individuals (e.g. Stattermayer_2019). These reports do not provide unequivocal conclusions about association of the variant with Wilson Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as benign/likely benign (n=5) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000029352	SCV000796670	likely benign	Wilson disease	2017-12-28	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000514302	SCV001150662	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000029352	SCV001268684	uncertain significance	Wilson disease	2018-07-10	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Nilou-Genome Lab	RCV000029352	SCV001652722	uncertain significance	Wilson disease	2021-05-18	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV000029352	SCV000606967	not provided	Wilson disease		no assertion provided	phenotyping only	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.	RCV000029352	SCV001456187	likely benign	Wilson disease	2020-04-15	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000514302	SCV001807861	likely benign	not provided		no assertion criteria provided	clinical testing