ClinVar Miner

Submissions for variant NM_004320.6(ATP2A1):c.1561G>A (p.Val521Ile)

gnomAD frequency: 0.00011  dbSNP: rs200092983
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478414 SCV000573456 uncertain significance not provided 2017-02-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ATP2A1 gene. The V521I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V521I variant is observed in 2/8646 (0.02%) alleles from individuals of East Asian background in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V521I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000639610 SCV000761189 uncertain significance Brody myopathy 2022-07-30 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 521 of the ATP2A1 protein (p.Val521Ile). This variant is present in population databases (rs200092983, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATP2A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423726). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Revvity Omics, Revvity RCV000639610 SCV003834363 uncertain significance Brody myopathy 2022-08-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV004023202 SCV004913380 uncertain significance Inborn genetic diseases 2023-09-26 criteria provided, single submitter clinical testing The c.1561G>A (p.V521I) alteration is located in exon 14 (coding exon 14) of the ATP2A1 gene. This alteration results from a G to A substitution at nucleotide position 1561, causing the valine (V) at amino acid position 521 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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