ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.1947-4C>T (rs74904335)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001721333 SCV000529873 likely benign not provided 2018-09-11 criteria provided, single submitter clinical testing
Invitae RCV000631244 SCV000752268 benign Wilson disease 2020-12-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000440735 SCV000918584 uncertain significance not specified 2017-10-05 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.1947-4C>T variant causes a missense change involving the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 159/275932 control chromosomes including two homozygous occurrences (gnomAD), predominantly observed in the East Asian subpopulation at a frequency of 0.008075 (152/18824). This frequency is about 1.5 times the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006), suggesting this is possibly a benign rare polymorphism found primarily in the populations of East Asian origin. Two studies report this variant as a polymorphism, without clearly stating if it was found in WD patients or controls (Kim_1998, Kim_1998). One clinical diagnostic laboratory has classified this variant as likely benign. Taken together, this variant is classified as VUS-possibly benign.
Illumina Clinical Services Laboratory,Illumina RCV000631244 SCV001267852 uncertain significance 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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