ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3889G>A (p.Val1297Ile) (rs148399850)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078053 SCV000109891 benign not specified 2013-11-20 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000078053 SCV000192353 benign not specified 2019-02-01 criteria provided, single submitter clinical testing
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490530 SCV000267217 uncertain significance Wilson disease 2016-03-18 criteria provided, single submitter reference population
GeneDx RCV000078053 SCV000520883 likely benign not specified 2017-12-15 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.
Invitae RCV000490530 SCV000752282 benign Wilson disease 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000755838 SCV000883436 likely benign not provided 2018-06-22 criteria provided, single submitter clinical testing The ATP7B c.3889G>A; p.Val1297Ile variant (rs148399850), is reported in the literature in as a neutral polymorphism in both individuals affected with Wilson Disease and unaffected individuals (Hua 2016, Loudianos 1999, Li 2011, Wan 2006). This variant is also reported in ClinVar (Variation ID: 92389). This variant is found in the East Asian population with an overall allele frequency of 1.7% (316/18870 alleles, including 6 homozygotes) in the Genome Aggregation Database. The valine at codon 1297 is weakly conserved, is found as an isoleucine in 3 of 12 vertebrate species, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Based on available information, this variant is considered to be likely benign.
Integrated Genetics/Laboratory Corporation of America RCV000078053 SCV000918600 benign not specified 2018-06-21 criteria provided, single submitter clinical testing Variant summary: ATP7B c.3889G>A (p.Val1297Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0027 in 279784 control chromosomes, predominantly at a frequency of 0.017 within the East Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3.15 fold of 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 East Asian origin. c.3889G>A has been reported as a "polymorphism" in the literature in individuals affected with Wilson Disease. Multiple studies reported not significantly different MAF of variant in diesease vs control cohort (Dong_2016 and Hua_2016) and listed variant as polymorphism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar without evidence for independent evaluation (2 benign, 2 likely benign and 1 VUS). Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000490530 SCV001139347 benign Wilson disease 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000490530 SCV001268482 likely benign Wilson disease 2018-09-17 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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