Submissions for variant NM_170665.4(ATP2A2):c.2104G>A (p.Asp702Asn)

dbSNP: rs2548563282

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003557787	SCV004296226	pathogenic	not provided	2023-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 702 of the ATP2A2 protein (p.Asp702Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Darier disease (PMID: 10441323, 15186327, 19528419; Invitae). 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 ATP2A2 protein function. Experimental studies have shown that this missense change affects ATP2A2 function (PMID: 12975374, 16766529). For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005251365	SCV005902190	pathogenic	Keratosis follicularis	2024-07-12	criteria provided, single submitter	clinical testing	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.