ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2731-2A>G (rs367956522)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169025 SCV000220173 likely pathogenic Wilson disease 2014-03-20 criteria provided, single submitter literature only
GeneDx RCV000485754 SCV000568297 pathogenic not provided 2017-01-20 criteria provided, single submitter clinical testing The c.2731-2A>G pathogenic variant in the ATP7B gene has been reported previously in the homozygous state in association with Wilson disease (Shah et al., 1997). This splice site variant destroys the canonical splice acceptor site in intron 11. Sequencing of mutant APT7B RNA shows exon 12 skipping as well as an insertion of 13 amino acids, due to the use of a cryptic splice acceptor site (Shah et al., 1997). The c.2731-2A>G variant was not observed with any significant frequency in approximately 6500 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 c.2731-2A>G as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000169025 SCV000694427 pathogenic Wilson disease 2016-07-19 criteria provided, single submitter clinical testing Variant summary: The ATP7B c.2731-2A>G variant located at a conserved intronic position, known to affect splicing with 5/5 splice prediction tools predicting a significant effect on splicing, which has been functionally supported (Shah_1997). This mutation produces 13 additional amino acids (VVISHGLGVLFSW) in the region between the transduction motif and the fifth Tm region. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/119818 (1/59909), which does not exceed the estimated maximal expected allele frequency for a pathogenic ATP7B variant of 1/185. Multiple publications cite the variant in affected individuals including a homozygous individual, along with a reputable clinical laboratory citing the variant as "likely pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Invitae RCV000169025 SCV000825192 pathogenic Wilson disease 2019-11-26 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 11 of the ATP7B gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs367956522, ExAC 0.009%). This variant has been observed as homozygous and in combination with another ATP7B variant in individuals affected with Wilson disease (PMID: 9311736, 23518715, Invitae). ClinVar contains an entry for this variant (Variation ID: 188725). Experimental studies have shown that this splice acceptor change disrupts splicing resulting in skipping exon 12 or the usage of a cryptic splice site and the insertion of 13 additional amino acids (PMID: 9311736). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Population and Evolutionary Genetics,University of Puerto Rico at Mayaguez RCV000169025 SCV000926218 pathogenic Wilson disease 2019-02-22 criteria provided, single submitter research dbSNP:rs367956522 in ATP7B has been reported segregating with Wilson's Disease in the UK with compound heterozygous in 3 cases (Coffey et al. 2013, PMID 23518715), and in the USA in both homozygous and compound heterozygous forms (Shah et al. 1997, PMID 9311736). In our unpublished study, all 4 individuals diagnosed with Wilson's Disease in southwestern Puerto Rico were homozygous for the minor allele. By contrast, none of the 214 healthy individuals tested were homozygous, In summary, dbSNP:rs367956522 is classified as pathogenic/likely pathogenic but meets our criteria to be classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000169025 SCV001159360 pathogenic Wilson disease 2018-07-25 criteria provided, single submitter clinical testing The ATP7B c.2731-2A>G variant (rs367956522) is reported in the literature in multiple individuals affected with Wilson disease (Bost 2012, Coffey 2013, Mukherjee 2014, Shah 1997). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 188725), and is found in the general population with an overall allele frequency of 0.002% (5/244900 alleles) in the Genome Aggregation Database. This variant abolishes the canonical splice acceptor site of intron 11, and has been shown to alter splicing, causing an in-frame insertion of 39 nucleotides (Shah 1997), which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. References: Bost M et al. Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. J Trace Elem Med Biol. 2012 Jun;26(2-3):97-101. Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. Mukherjee S et al. Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation. Parkinsonism Relat Disord. 2014 Jan;20(1):75-81. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.