ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1905C>A (p.Asn635Lys) (rs1414146587)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780271 SCV000917398 pathogenic Glycogen storage disease, type II 2018-10-26 criteria provided, single submitter clinical testing Variant summary: GAA c.1905C>A (p.Asn635Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 237820 control chromosomes. c.1905C>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect was estimated to result in 10%-<30% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000780271 SCV001422990 likely pathogenic Glycogen storage disease, type II 2020-01-15 no assertion criteria provided curation The p.Asn635Lys variant in GAA has been reported in at least 5 individuals with glycogen storage disease II (PMID: 19588081, 22644586, 22658377) and has been identified in 0.003% (1/33926) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1414146587). 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 using cells transfected with the variant provide some evidence that the p.Asn635Lys variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been reported in the homozygous state and in combination with reported pathogenic variants in multiple individuals with glycogen storage disease II (PMID: 19588081, 22658377). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2 (Richards 2015).

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