Submissions for variant NM_170665.4(ATP2A2):c.94C>T (p.Leu32Phe)

gnomAD frequency: 0.00048  dbSNP: rs141335001

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000403131	SCV000376226	benign	Keratosis follicularis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002522220	SCV003259496	uncertain significance	not provided	2023-02-13	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt ATP2A2 protein function. ClinVar contains an entry for this variant (Variation ID: 307160). This missense change has been observed in individual(s) with Darier disease (PMID: 21519848, 23356892, 30345710). This variant is present in population databases (rs141335001, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 32 of the ATP2A2 protein (p.Leu32Phe).
Molecular Genetics, Royal Melbourne Hospital	RCV000403131	SCV004812607	uncertain significance	Keratosis follicularis	2023-06-06	criteria provided, single submitter	clinical testing	This sequence change in ATP2A2 is predicted to replace leucine with phenylalanine at codon 32, p.(Leu32Phe). The leucine residue is moderately conserved (100 vertebrates, UCSC), and is located in the cation ATPase N domain. There is a small physicochemical difference between leucine and phenylalanine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.05% (53/107,582 alleles) in the European (non-Finnish) population. This variant has been reported in at least one individual with a diagnosis of Darier's disease (PMID: 23356892). Computational evidence predicts a benign effect for the missense substitution (REVEL = 0.213). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: BP4.