ClinVar Miner

Submissions for variant NM_000053.4(ATP7B):c.2975C>T (p.Pro992Leu) (rs201038679)

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 RCV000169179 SCV000220416 pathogenic Wilson disease 2014-06-14 criteria provided, single submitter literature only
GeneDx RCV000362786 SCV000329794 pathogenic not provided 2015-12-27 criteria provided, single submitter clinical testing The P992L pathogenic variant in the ATP7B gene has been reported previously in several individuals of Japanese ancestry with Wilson disease, either in the homozygous state or compound heterozygous with another missense or nonsense variant (Nanji et al., 1997; Gu et al., 2013). This variant was not observed in approximately 6200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This variant occurs in a transmembrane domain and predicted cation channel of the ATP7B gene, and functional studies demonstrate that the P992L variant results in compromised cellular copper tolerance and excretion (Zhu et al., 2015). The P992L variant is a semi-conservative amino acid substitution which occurs at a position that is conserved across species. Several missense variants in the same and nearby residues (G988R, G988E, A990P, T991M, P992H, T993M, V995A, and M996T) have been reported in the Human Gene Mutation Database in association with Wilson disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret P992L as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000169179 SCV000894015 pathogenic Wilson disease 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000169179 SCV000916639 pathogenic Wilson disease 2018-11-12 criteria provided, single submitter clinical testing Variant summary: ATP7B c.2975C>T (p.Pro992Leu) results in a non-conservative amino acid change in the predicted cation chanel TM6 domain of the encoded protein sequence. Another variant in the same codon c.2975C>A (p.P992H) has been reported to be associated with Wilson Disease (HGMD; Kumar et al., Clin Genet, 2005; Schushan et al. Metallomics, 2012). Five of five in-silico tools predict a damaging effect of the variant on protein function. This mutation is predicted to disrupt the function of the cation channel and/or the formation of the transmembrane domain. The variant allele was found at a frequency of 3.6e-05 in 276312 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (3.6e-05 vs 0.0054), allowing no conclusion about variant significance. c.2975C>T has been reported in the literature in multiple individuals affected with Wilson Disease (Dong_2016) with homozygous or compound heterozygous genotypes. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169179 SCV000944460 pathogenic Wilson disease 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 992 of the ATP7B protein (p.Pro992Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs201038679, ExAC 0.05%). This variant has been observed in several individuals and families affected with Wilson disease (PMID: 23843956). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188831). This variant has been reported to affect ATP7B protein function (PMID: 9837819). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000169179 SCV001158016 pathogenic Wilson disease 2018-11-15 criteria provided, single submitter clinical testing The ATP7B c.2975C>T; p.Pro992Leu variant (rs201038679), is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with Wilson disease (Gu 2013, Nanji 1997, Seidel 2001, Wu 2006, Yu 2017). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 188831), and is found in the East Asian population with an allele frequency of 0.046% (9/19,520 alleles) in the Genome Aggregation Database. The proline at codon 992 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate impaired protein trafficking and decreased copper transport activity (Huster 2012, Zhu 2015). Based on available information, the p.Pro992Leu variant is considered to be pathogenic. References: Gu S et al. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson's disease. PLoS One. 2013 Jul 2;8(7):e66526. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. Nanji MS et al. Haplotype and mutation analysis in Japanese patients with Wilson disease. Am J Hum Genet. 1997 Jun;60(6):1423-9. Seidel J et al. Disturbed copper transport in humans. Part 2: mutations of the ATP7B gene lead to Wilson disease (WD). Cell Mol Biol (Noisy-le-grand). 2001;47 Online Pub:OL149-57. Wu ZY et al. Mutation analysis of 218 Chinese patients with Wilson disease revealed no correlation between the canine copper toxicosis gene MURR1 and Wilson disease. J Mol Med (Berl). 2006 May;84(5):438-42. Yu H et al. Clinical features and outcome in patients with osseomuscular type of Wilson's disease. BMC Neurol. 2017 Feb 17;17(1):34. Zhu M et al. Defective roles of ATP7B missense mutations in cellular copper tolerance and copper excretion. Mol Cell Neurosci. 2015 Jul;67:31-6.

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.