ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.51+4A>T (rs369488210)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000324263 SCV000384689 pathogenic Wilson disease 2017-04-28 criteria provided, single submitter clinical testing The ATP7B c.51+4A>T splice-region variant has been described in eight studies in which it was found in a total of 11 patients with Wilson disease including in three in a homozygous state (including two siblings) and in 11 in a compound heterozygous state (including two pairs of siblings) (Deguti et al. 2004; Lovicu et al. 2009; Nicastro et al. 2009; Nicastro et al. 2010; Bost et al. 2012; Bem et al. 2013; Arruda et al. 2014; Paradisi et al. 2014). The c.51+4A>T variant was absent from 108 controls but is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. One functional study demonstrated that the c.51+4A>T variant did not result in aberrant splicing (Deguti et al. 2004). Lovicu et al. (2004) however showed that the variant resulted in aberrant splicing in individuals who were homozygous for the variant but not in compound heterozygotes (Lovicu et al. 2009). Based on the collective evidence, the c.51+4A>T variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000324263 SCV000934383 pathogenic Wilson disease 2019-09-29 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the ATP7B gene. It does not directly change the encoded amino acid sequence of the ATP7B protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs369488210, ExAC 0.005%). This variant has been observed in several individuals and families affected with ATP7B-related conditions (PMID: 19371217, 23962630, 15024742, 25497208, 20967755). ClinVar contains an entry for this variant (Variation ID: 312401). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change has a deleterious effect on splicing (PMID: 19371217). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000324263 SCV001139359 pathogenic Wilson disease 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000324263 SCV001432117 pathogenic Wilson disease 2020-08-21 criteria provided, single submitter clinical testing Variant summary: ATP7B c.51+4A>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports splicing assay performed on the patients blood sample showed partial splicing defect (Lovicu_2009). The variant allele was found at a frequency of 1.6e-05 in 249536 control chromosomes (gnomAD and publication data). c.51+4A>T has been reported in the literature in the compound heterozygous or homozygous state in multiple individuals affected with Wilson Disease (Deguti_2004, Margarit_2005, Lovicu_2009, Coffey_2013, Paradisi_2014). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (3x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000324263 SCV000790779 likely pathogenic Wilson disease 2017-04-07 no assertion criteria provided clinical testing

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