Submissions for variant NM_000053.4(ATP7B):c.3008C>T (p.Ala1003Val)

dbSNP: rs775055397

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169109	SCV000220309	likely pathogenic	Wilson disease	2014-05-14	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169109	SCV001361702	pathogenic	Wilson disease	2019-12-09	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3008C>T (p.Ala1003Val) results in a non-conservative amino acid change in 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 3.3e-05 in 240390 control chromosomes (gnomAD). c.3008C>T has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Loudianos_1999, Coffey_2013, Guggilla_2015). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000169109	SCV001592608	pathogenic	Wilson disease	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1003 of the ATP7B protein (p.Ala1003Val). This variant is present in population databases (rs775055397, gnomAD 0.03%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 17264425, 31059521). ClinVar contains an entry for this variant (Variation ID: 188781). 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) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. This variant disrupts the p.Ala1003 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12885331, 21610751, 26799313; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508716	SCV001715051	likely pathogenic	not provided	2020-09-04	criteria provided, single submitter	clinical testing	PS4_moderate, PM2, PM5, PP4
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814079	SCV001755451	likely pathogenic	Abnormality of metabolism/homeostasis	2021-07-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169109	SCV001977286	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169109	SCV002811654	pathogenic	Wilson disease	2022-01-13	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000169109	SCV004032255	pathogenic	Wilson disease	2023-08-25	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PS4_MOD,PP3; Identified as compund heterozygous with NM_000053.4:c.2906G>A
Baylor Genetics	RCV000169109	SCV004216277	likely pathogenic	Wilson disease	2023-10-22	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000169109	SCV001469299	pathogenic	Wilson disease	2020-10-11	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169109	SCV002086833	pathogenic	Wilson disease	2018-01-05	no assertion criteria provided	clinical testing