ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2304dup (p.Met769fs) (rs137853287)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000543563 SCV000626841 pathogenic Wilson disease 2019-10-29 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 8 of the ATP7B mRNA (c.2304dupC), causing a frameshift at codon 769. This creates a premature translational stop signal (p.Met769Hisfs*26) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic. This particular variant has been reported as heterozygous co-occurring with other ATP7B variants in multiple individuals affected with Wilson disease (PMID: 24897373, 21796144, 22735241, 15024742, 20517649, 25390358, Invitae database). This variant has also been reported as homozygous in 5 affected individuals in a family affected with Wilson disease (PMID: 25390358). In addition, family studies have shown that this variant co-segregated with disease (PMID: 25390358, 24897373). ClinVar contains an entry for this variant (Variation ID: 156282) with alternative nomenclature. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000543563 SCV000694419 pathogenic Wilson disease 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.2304dupC (p.Met769Hisfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2336G>A, p.Trp779X; c.3402delC, p.Ala1135fs). One in silico tool predicts a damaging outcome for this variant. One functional study showed more than 50% decrease in ATPase activity in lymphoblasts a WD homozygote patient (Shah_AJHG_1997). The variant of interest has been found in a large, broad control population, ExAC in 8/120692 control chromosomes at a frequency of 0.0000663, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). This variant has been reported in different cohorts of WD patients (heterozygotes and homozygotes) and is a known common disease variant present in 6% of Croatian patients and 8% Mediterranean populations (Sardinian, continental Italian, Turkish, Albanian)(Figus_AJHG_1995, Ljubic_Genetic Testing and Molecular Biomarkers_2016). In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000623842 SCV000742289 pathogenic Inborn genetic diseases 2016-12-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000543563 SCV001157629 pathogenic Wilson disease 2019-04-05 criteria provided, single submitter clinical testing The ATP7B c.2304dupC; p.Met769fs variant (rs137853287), also known as 2299insC or 2304_2305insC, is a recurrent alteration found in patients diagnosed with Wilson disease and is reported to co-segregate with disease (Cocos 2014, Hua 2016, Thomas 1995, Usta 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 456552). It is found in the general population with an overall allele frequency of 0.01% (32/280946 alleles) in the Genome Aggregation Database. This variant causes a frameshift by duplicating a single nucleotide, so it 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 Cocos R et al. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity. PLoS One. 2014 Jun 4;9(6):e98520. Hua R et al. Mutational analysis of ATP7B in Chinese Wilson disease patients. Am J Transl Res. 2016 Jun 15;8(6):2851-61. Thomas GR et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995 Feb;9(2):210-7. Usta J et al. Phenotype-genotype correlation in Wilson disease in a large Lebanese family: association of c.2299insC with hepatic and of p. Ala1003Thr with neurologic phenotype. PLoS One. 2014 Nov 12;9(11):e109727.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196444 SCV001367052 pathogenic Neurodevelopmental disorder 2019-10-08 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001200388 SCV001371335 pathogenic not provided 2020-06-01 criteria provided, single submitter clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000543563 SCV000189433 not provided Wilson disease no assertion provided not provided
Counsyl RCV000543563 SCV000678185 pathogenic Wilson disease 2014-02-14 no assertion criteria provided clinical testing

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