ClinVar

Description

An ATP2A2 c.2104G>A (p.Asp702Asn) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported as germline in multiple individuals affected with Darier disease (Gordon-Smith K et al., PMID: 30345710; Bchetnia M et al., PMID: 19528419; Miyauchi Y et al., PMID: 16766529; Dodiuk-Gad R et al., PMID: 26471493; Dode L et al., PMID: 12975374; Rácz E et al., PMID: 15186327; Green E et al., PMID: 23356892). This variant has been reported in the ClinVar database as a pathogenic germline variant by one submitter (ClinVar ID: 2735974). The ATP2A2 c.2104G>A (p.Asp702Asn) variant is absent from the general population database (gnomAD v4.1.0), indicating it is not a common variant. This variant resides within a highly conserved region of the hinge domain of ATP2A2 that is implicated in the binding and transfer of phosphate to the protein and in the transport-associated conformational changes of the phosphorylation site (Vilsen B et al., PMID: 1831454). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on ATP2A2 function. In support of this prediction, functional studies show that the ATP2A2 c.2104G>A (p.Asp702Asn) variant reduced SERCA2 enzyme activity and impaired calcium transport into the endoplasmic reticulum in cell lines, indicating that this variant impacts protein function (Miyauchi Y et al., PMID: 16766529; Dode L et al., PMID: 12975374). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation (Leon-Quintero FZ et al., PMID: 39434542), the ATP2A2 c.2104G>A (p.Asp702Asn) variant is classified as pathogenic.