ClinVar Miner

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

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Total submissions: 13
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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

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