ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.3556G>A (p.Gly1186Ser) (rs786204547)

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Total submissions: 3
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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 2020-04-22 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000169260 SCV001473759 pathogenic Wilson disease 2019-11-22 criteria provided, single submitter clinical testing The ATP7B c.3556G>A; p.Gly1186Ser variant (rs786204547) is reported in the medical literature in several individuals with a clinical diagnosis of Wilson disease (Lepori 2012, Park 2007, Tatsumi 2010), and has been reported in Wilson disease patients with an additional pathogenic variant (Seo 2012, Yamaguchi 1998). Furthermore, two other variants at the same codon (p.Gly1186Arg and p.Gly1186Ser) have been described in individuals with Wilson Disease (Mukherjee 2014, Shah 1997). The p.Gly1186Ser variant is reported in the ClinVar database (Variation ID: 188900) and is only described on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 1186 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, this variant is located at the last nucleotide of exon 16. Computational splicing analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, and functional analysis of patient RNA shows skipping of exon 16 (Okada 2010). Based on available information, this variant is considered to be pathogenic. References: Lepori MB et al. Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: contribution to diagnosis. Mol Cell Probes. 2012 Aug;26(4):147-50. Mukherjee S et al. Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation. Parkinsonism Relat Disord. 2014 Jan;20(1):75-81. Okada T et al. High prevalence of fulminant hepatic failure among patients with mutant alleles for truncation of ATP7B in Wilson's disease. Scand J Gastroenterol. 2010 Oct;45(10):1232-7. Park S et al. Identification of novel ATP7B gene mutations and their functional roles in Korean patients with Wilson disease. Hum Mutat. 2007 Nov;28(11):1108-13. Seo J. Diagnosis of Wilson disease in young children: molecular genetic testing and a paradigm shift from the laboratory diagnosis. Pediatr Gastroenterol Hepatol Nutr. 2012 Dec;15(4):197-209. Shah AB et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997 Aug;61(2):317-28. Tatsumi Y et al. Current state of Wilson disease patients in central Japan. Intern Med. 2010;49(9):809-15. Yamaguchi A et al. Mutations of ATP7B gene in Wilson disease in Japan: identification of nine mutations and lack of clear founder effect in a Japanese population. Hum Mutat. 1998;Suppl 1:S320-2.

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