Submissions for variant NM_000053.4(ATP7B):c.3818C>A (p.Pro1273Gln)

dbSNP: rs758355520

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668789	SCV000793447	likely pathogenic	Wilson disease	2017-08-16	criteria provided, single submitter	clinical testing
Invitae	RCV000668789	SCV001222918	pathogenic	Wilson disease	2023-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 1273 of the ATP7B protein (p.Pro1273Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Wilson disease (PMID: 16696937, 18483695, 25465132, 27398169). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 553360). 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. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22692182). This variant disrupts the p.Pro1273 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15024742, 17272994, 20485189, 23551039). 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.
Genome-Nilou Lab	RCV000668789	SCV001977231	likely pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668789	SCV002500148	pathogenic	Wilson disease	2022-03-07	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3818C>A (p.Pro1273Gln) 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 was absent in 249564 control chromosomes (gnomAD). c.3818C>A has been reported in the literature in two homozygous individuals affected with Wilson Disease (example: El-Mougy_2014) and the variant seggregated with the disease. These data indicate that the variant is likely to be associated with disease. Schushan_2012 demonstrated that P1273 changes to S/L/Q leads to very low copper uptake. Another variant affecting the same codon has been classified as pathogenic by our lab (p.Pro1273Leu). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.