ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2827G>A (p.Gly943Ser) (rs28942076)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000004060 SCV000694432 pathogenic Wilson disease 2016-02-16 criteria provided, single submitter clinical testing Variant summary: c.2827G>A affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 2/120362 control chromosomes at a frequency of 0.0000166, which does not exceed maximal expected frequency of a pathogenic allele (0.0054006). This variant has been reported in multiple affected individuals and functional studies showed that variant had impaired ability to complement the high-affinity iron-uptake deficiency of the yeast mutant, and despite the normal localization of variant to the Golgi network of CHO cells, variant was non-responsive to copper and exhibited no obvious copper-induced redistribution (Forbes_1998 and 2000). Taken together, this variant was classified as a Pathogenic.
Invitae RCV000004060 SCV000959367 pathogenic Wilson disease 2019-03-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 943 of the ATP7B protein (p.Gly943Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs28942076, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 7626145, 11243728, 27022412). ClinVar contains an entry for this variant (Variation ID: 3856). Experimental studies have shown that this missense change disrupts redistribution of ATP7B protein in response to copper (PMID: 10942420). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Gly943 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 28212618, 16603785, 27930511, 16088907), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001091638 SCV001247797 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing
OMIM RCV000004060 SCV000024226 pathogenic Wilson disease 1995-02-01 no assertion criteria provided literature only
Counsyl RCV000004060 SCV000793725 likely pathogenic Wilson disease 2019-01-22 no assertion criteria provided clinical testing

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