ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1465G>A (p.Asp489Asn) (rs398123169)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790665 SCV000224781 pathogenic not provided 2013-03-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000173646 SCV000695644 pathogenic Glycogen storage disease, type II 2017-06-30 criteria provided, single submitter clinical testing Variant summary: The GAA c.1465G>A (p.Asp489Asn) variant involves the alteration of a conserved nucleotide located in the Glycoside hydrolase superfamily domain of the protein (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 2/120924 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205). This variant has been reported in multiple affected individuals and GAA activity testing confirm the variant results in deficiency. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl RCV000173646 SCV000791020 likely pathogenic Glycogen storage disease, type II 2017-04-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000173646 SCV000894161 likely pathogenic Glycogen storage disease, type II 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000173646 SCV001213830 pathogenic Glycogen storage disease, type II 2019-12-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 489 of the GAA protein (p.Asp489Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs398123169, ExAC 0.009%). This variant has been observed in individual(s) with glycogen storage disease type II (GSDII) (PMID: 16917947, 24844452, 29422078). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92465). This variant has been reported to affect GAA protein function (PMID: 16917947). For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000790665 SCV001245688 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000173646 SCV001423066 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Asp489Asn variant in GAA has been reported in 15 individuals (including 9 Italian, 1 Spanish, and 1 French individuals) with Glycogen Storage Disease II (PMID: 22081099, 17616415, 18429042, 22711147, 22658377, 24844452, 22980766, 25103075; DOI: 10.12032/TMRTH201804005), and has also been reported likely pathogenic by Counsyl and Fulgent Genetics and pathogenic by EGL Genetic Diagnostics and Integrated Genetics in ClinVar (Variation ID: 92465). This variant has been identified in 0.004621% (1/21638) of European (Finnish) chromosomes, 0.003% (1/30614) of South Asian chromosomes, and 0.001% (1/113488) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123169). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Asp489Asn variant may impact GAA activity (PMID: 19862843). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with pathogenic and likely pathogenic variants and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Asp489Asn variant is pathogenic (PMID: 22658377, 22081099; 10.12032/TMRTH201804005). The phenotype of individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity detected by assays with relevant tissue (PMID: 17151339, 22658377, 22081099, 17616415; DOI: 10.12032/TMRTH201804005). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies with COS cells transfected with this variant and multiple occurrences with pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3, PM2, PP3, PP4 (Richards 2015).

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