Submissions for variant NM_000053.4(ATP7B):c.3895C>T (p.Leu1299Phe)

dbSNP: rs749472361

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169572	SCV000221072	likely pathogenic	Wilson disease	2015-01-22	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169572	SCV000626861	pathogenic	Wilson disease	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1299 of the ATP7B protein (p.Leu1299Phe). This variant is present in population databases (rs749472361, gnomAD 0.03%). This missense change has been observed in individual(s) with Kayser-Fleischer rings and plasma ceruloplasmin <= 20 mg/dL, findings that are highly specific for Wilson disease (PMID: 24094725). ClinVar contains an entry for this variant (Variation ID: 189149). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000169572	SCV001977227	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000169572	SCV002021998	likely pathogenic	Wilson disease	2021-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169572	SCV002570653	pathogenic	Wilson disease	2022-07-22	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3895C>T (p.Leu1299Phe) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 249420 control chromosomes (gnomAD). c.3895C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Wilson Disease (examples: Mukherjee_2014 and Aggarwal_2013). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=3)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000169572	SCV002809461	likely pathogenic	Wilson disease	2021-11-21	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000169572	SCV004100917	likely pathogenic	Wilson disease		criteria provided, single submitter	clinical testing	The missense variant p.L1299F in ATP7B (NM_000053.4) causes the same amino acid change as a previously established pathogenic variant. The p.L1299F variant is observed in 9/30,602 (0.0294%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.L1299F missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.3895 in ATP7B is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV000169572	SCV004216402	pathogenic	Wilson disease	2024-03-20	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000169572	SCV005687695	pathogenic	Wilson disease	2025-02-03	criteria provided, single submitter	clinical testing
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000169572	SCV005873659	pathogenic	Wilson disease	2020-08-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169572	SCV001455577	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751319	SCV005343336	pathogenic	ATP7B-related disorder	2024-03-22	no assertion criteria provided	clinical testing	The ATP7B c.3895C>T variant is predicted to result in the amino acid substitution p.Leu1299Phe. This variant has been reported in both the homozygous and stated compound heterozygous state in individuals, particularly of Indian descent, with Wilson disease (Santhosh et al. 2006. PubMed ID: 17264425; Mukherjee et al. 2013. PubMed ID: 24094725; Aggarwal et al. 2013. PubMed ID: 23551039; Nayagam et al. 2022. PubMed ID: 36096368). This variant is reported in 0.029% of alleles in individuals of South Asian descent in gnomAD and has been consistently interpreted as pathogenic and likely pathogenic by other laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/189149/). Additionally, a different missense change impacting the same amino acid (c.3896T>G, p.Leu1299Arg) was observed in an individual from a Wilson disease cohort study (Table 2, Dong et al. 2016. PubMed ID: 27022412). Taken together, this variant is interpreted as pathogenic.