Submissions for variant NM_000053.4(ATP7B):c.2383C>T (p.Leu795Phe) (rs751710854)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169151	SCV000220376	likely pathogenic	Wilson disease	2014-06-04	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169151	SCV000694422	pathogenic	Wilson disease	2016-06-07	criteria provided, single submitter	clinical testing	Variant summary: The c.2383C>T (p.Leu795Phe) in ATP7B gene is a missense change that involves a conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant is present in the control population dataset of ExAC at frequency of 0.00003 (4/120764 chrs tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0054. The variant was identified homozygously and in compound heterozygosity in several WD pts. In functional studies the variant displayed features of mild mutation. The variant of interest has been reported as Likely Pathogenic by another clinical laboratory, without evidence to independently evaluate. Taking together, the variant was classified as Pathogenic.
Invitae	RCV000169151	SCV000815245	pathogenic	Wilson disease	2020-07-27	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with phenylalanine at codon 795 of the ATP7B protein (p.Leu795Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs751710854, ExAC 0.01%). This variant has been observed to be homozygous and in combination with another ATP7B variant in several individuals affected with Wilson disease (WD) (PMID: 23551039, 17264425). This variant has been observed in additional individuals with WD (PMID: 9311736, 23235335, 24094725, 26207595, 27022412). ClinVar contains an entry for this variant (Variation ID: 188814). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). For these reasons, this variant has been classified as Pathogenic. 5
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000169151	SCV001472172	likely pathogenic	Wilson disease	2019-08-28	criteria provided, single submitter	clinical testing	The ATP7B c.2383C>T; p.Leu795Phe variant (rs751710854) is reported in the literature in multiple individuals affected with Wilson disease, including in the homozygous or compound heterozygous state (Aggarwal 2013, Dong 2016, Li 2013, Mukherjee 2014, Santhosh 2006, Shah 1997). This variant is reported in ClinVar (Variation ID: 188814), and is only observed on seven alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 795 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.2384T>G; p.Leu795Arg) have been reported in individuals with Wilson disease (Curtis 1999). Based on available information, this variant is considered to be likely pathogenic. References: Aggarwal A et al. Wilson disease mutation pattern with genotype-phenotype correlations from Western India: confirmation of p.C271* as a common Indian mutation and identification of 14 novel mutations. Ann Hum Genet. 2013 Jul;77(4):299-307. Curtis D et al. A study of Wilson disease mutations in Britain. Hum Mutat. 1999;14(4):304-11. Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients with Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. Li K et al. Mutational analysis of ATP7B in north Chinese patients with Wilson disease. J Hum Genet. 2013 Feb;58(2):67-72. Mukherjee S et al. Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation. Parkinsonism Relat Disord. 2014 Jan;20(1):75-81. Santhosh S et al. ATP7B mutations in families in a predominantly Southern Indian cohort of Wilson's disease patients. Indian J Gastroenterol. 2006 Nov-Dec;25(6):277-82. 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.
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City	RCV000169151	SCV001133003	pathogenic	Wilson disease	2019-09-15	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169151	SCV001459727	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing