ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.795T>A (p.Ser265Arg)

gnomAD frequency: 0.00001  dbSNP: rs779785396
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV002261579 SCV002541439 uncertain significance not provided 2021-12-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003095878 SCV003253457 uncertain significance Glycogen storage disease, type II 2022-06-24 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 265 of the GAA protein (p.Ser265Arg). This variant is present in population databases (rs779785396, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. 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 GAA protein function. 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 RCV002261579 SCV003834053 uncertain significance not provided 2020-02-12 criteria provided, single submitter clinical testing
Molecular Genetics, Royal Melbourne Hospital RCV003095878 SCV004812705 uncertain significance Glycogen storage disease, type II 2023-03-30 criteria provided, single submitter clinical testing This sequence change in GAA is predicted to replace serine with arginine at codon 265, p.(Ser265Arg). The serine residue is weakly conserved (100 vertebrates, UCSC), and is not located in an annotated functional domain. There is a large physicochemical difference between serine and arginine. The highest population minor allele frequency in gnomAD v2.1 is 0.003% (3/113,280 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. To our knowledge, this variant has not been reported in the literature in any individuals with GAA-related disease. Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict benign). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting.

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