Submissions for variant NM_004320.6(ATP2A1):c.2464del (p.Arg822fs)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529448	SCV000638290	pathogenic	Brody myopathy	2024-09-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg822Glyfs*49) in the ATP2A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP2A1 are known to be pathogenic (PMID: 8841193, 10914677, 23911890). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 464084). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000598570	SCV000710210	likely pathogenic	not provided	2017-12-14	criteria provided, single submitter	clinical testing	The c.2464delC variant in the ATP2A1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.2464delC variant causes a frameshift starting with codon Arginine 822, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 49 of the new reading frame, denoted p.Arg822GlyfsX49. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2464delC variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.2464delC as a likely pathogenic variant.
Revvity Omics, Revvity	RCV000529448	SCV002024417	likely pathogenic	Brody myopathy	2019-04-16	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000529448	SCV002578909	likely pathogenic	Brody myopathy	2022-03-24	criteria provided, single submitter	clinical testing

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