ClinVar Miner

Submissions for variant NM_000053.3(ATP7B):c.3556G>A (p.Gly1186Ser) (rs786204547)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169260 SCV000220550 likely pathogenic Wilson disease 2014-07-24 criteria provided, single submitter literature only
Invitae RCV000169260 SCV000752259 pathogenic Wilson disease 2017-12-06 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1186 of the ATP7B protein (p.Gly1186Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant also falls at the last nucleotide of exon 16 of the ATP7B coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in combination with other ATP7B variants in individuals affected with Wilson's disease (PMID: 20491539, 18371106, 24010089, Invitae). In addition, this variant has been observed on the opposite chromosome (in trans) from other ATP7B pathogenic variants in individuals affected with Wilson's disease (PMID: 9452121). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease.  ClinVar contains an entry for this variant (Variation ID: 188900). This variant is also know as p.G1187S in the literature. Analysis of patient liver RNA shows that this variant is associated with exon 16 skipping  (PMID: 20491539). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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