ClinVar Miner

Submissions for variant NM_004320.6(ATP2A1):c.1287G>A (p.Glu429=)

gnomAD frequency: 0.00001  dbSNP: rs200596448
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658413 SCV000780185 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing The c.1287 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1287 G>A variant is not observed in large population cohorts (Lek et al., 2016). Several in silico splice prediction models predict that c.1287 G>A damages the natural splice donor site of intron 11 which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. 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 RCV001816658 SCV004344791 uncertain significance Brody myopathy 2024-01-04 criteria provided, single submitter clinical testing This sequence change affects codon 429 of the ATP2A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATP2A1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs200596448, gnomAD 0.006%). This variant has been observed in individual(s) with clinical features of Brody myopathy (PMID: 30688039). ClinVar contains an entry for this variant (Variation ID: 546520). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 11 and introduces a premature termination codon (PMID: 30688039). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
OMIM RCV001816658 SCV002064304 pathogenic Brody myopathy 2022-01-26 no assertion criteria provided literature only

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