ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.314C>A (p.Ser105Ter) (rs753236073)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169629 SCV000221158 likely pathogenic Wilson disease 2015-02-27 criteria provided, single submitter literature only
GeneDx RCV000293037 SCV000329798 pathogenic not provided 2016-02-28 criteria provided, single submitter clinical testing The S105X variant in the S105X gene has been reported previously in a Hong Kong Chinese patient with Wilson disease who was compound heterozygous for the S105X variant and another loss-of-function variant (Lam et al., 2006; Mak et al., 2008). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The S105X variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret S105X as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169629 SCV000694438 pathogenic Wilson disease 2016-04-25 criteria provided, single submitter clinical testing Variant summary: The variant c.314C>A leads to a nonsense mutation resulting in a stop codon at amino acid position 105 in the 1465 amino acid long ATP7B protein. This variant is therefore predicted to lead to a truncated or absent protein. Mutation Taster predicts disease-causing outcome for this substitution. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00082% which does not exceed the maximal expected allele frequency of a disease causing ATP7B allele (0.54%). The variant was reported in several Wilson disease patients mainly from China, including compound heterozygosity with pathogenic/potentially pathogenic ATP7B variants strongly indicating a pathogenic outcome. One reputable database (HGMD) classifies the variant as pathogenic and one clinical diagnostic center also classifies it as Likely Pathogenic in ClinVar. Considering all evidence, the variant has been classified as a Disease Variant or Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000169629 SCV000883441 pathogenic Wilson disease 2019-05-14 criteria provided, single submitter clinical testing The ATP7B c.314C>A; p.Ser105Ter variant (rs753236073) is reported in the literature in the compound heterozygous state in individuals affected with Wilson disease (Genschel 2000, Huong 2018, Mak 2008, Wang 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 189193), and is only observed twice in the Genome Aggregation Database general population database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Genschel J et al. Three novel mutations, c314C>A, C778insC, and c1285+2T>A, in exon 2 of the Wilson disease gene. Hum Mutat. 2000; 16(3):278. Huong NTM et al. Three novel mutations in the ATP7B gene of unrelated Vietnamese patients with Wilson disease. BMC Med Genet. 2018 Jun 18;19(1):104. Mak C et al. Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity. J Hum Genet. 2008; 53(1):55-63. Wang L et al. Mutation analysis of 73 southern Chinese Wilson's disease patients: identification of 10 novel mutations and its clinical correlation. J Hum Genet. 2011; 56(9):660-5.
Invitae RCV000169629 SCV000935466 pathogenic Wilson disease 2020-07-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser105*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs753236073, ExAC 0.01%). This variant has been observed in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 16510432, 29914392), and has been shown to segregate with disease in a family (PMID: 21796144). ClinVar contains an entry for this variant (Variation ID: 189193). 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. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.

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