Submissions for variant NM_000053.4(ATP7B):c.2519C>T (p.Pro840Leu)

gnomAD frequency: 0.00001  dbSNP: rs768671894

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000333003	SCV000329796	pathogenic	not provided	2016-03-15	criteria provided, single submitter	clinical testing	The P840L pathogenic variant in the ATP7B gene has been reported previously in several individuals with Wilson disease (Loudiano et al., 1998; Huster et al., 2012; Gu et al., 2013). This 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. The P840L variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. In-silico analysis predicts this variant is probably damaging to the protein structure/function, and functional studies demonstrate that the P840L variant results in impaired copper uptake (Huster et al., 2012). Missense variants in nearby residues (G836E, D842N, D842Y, G843R) 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 P840L as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169233	SCV000694424	pathogenic	Wilson disease	2016-09-22	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest affects a conserved nucleotide and results in replacing a small and kink-inducing Proline residue with a bulky and hydrophobic Leucine. 5/5 in silico prediction tools predict deleterious outcome by this substitution. The variant was found in the broad and large cohort of ExAC at an allele frequency of 1/120734 (0.0008%), which does not exceed the maximal expected allele frequency of a disease causing ATP7B allele (0.54%), further supporting a pathogenic nature for the variant. In addition, there are several Wilsons Disease patients reported to have the variant in compound heterozygote module (Amson_2012, Gu_2013, Nicastro_2010). Independent functional studies have shown that the variant results in the impairment of cellular copper transfer (Huster_2012 , Schushan_2012), which is consistent with a disease causing outcome. Considering all evidence, the variant was classified as pathogenic.
Invitae	RCV000169233	SCV001378716	pathogenic	Wilson disease	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 840 of the ATP7B protein (p.Pro840Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 17272994, 22720273, 23843956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188879). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP7B protein function. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22240481, 22692182). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000169233	SCV001477569	pathogenic	Wilson disease	2019-10-22	criteria provided, single submitter	clinical testing	The ATP7B c.2519C>T; p.Pro840Leu variant (rs768671894) is reported in the literature in individuals affected with Wilson disease, including multiple individuals that carried a second pathogenic variant (Amson 2012, Gu 2013, Loudianos 1998, Nicastro 2010). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 840 is highly conserved, and functional studies indicate that this variant has substantially decreased copper transport activity (Huster 2012). Based on available information, this variant is considered to be pathogenic. References: Amson M et al. Alagille syndrome and Wilson disease in siblings: a diagnostic conundrum. Can J Gastroenterol. 2012 Jun;26(6):330-2. 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. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. Nicastro E et al. Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease. Hepatology. 2010 Dec;52(6):1948-56.
Genome-Nilou Lab	RCV000169233	SCV001977314	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169233	SCV002784630	pathogenic	Wilson disease	2021-09-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169233	SCV004216337	pathogenic	Wilson disease	2023-09-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000169233	SCV000220503	pathogenic	Wilson disease	2019-06-27	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169233	SCV002087845	pathogenic	Wilson disease	2020-09-29	no assertion criteria provided	clinical testing