ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1935C>A (p.Asp645Glu) (rs28940868)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Miraca Genetics Laboratories, RCV000055768 SCV000807221 pathogenic Glycogen storage disease, type II 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a pathogenic variant in a 1-year-old female with infantile Pompe disease
Counsyl RCV000055768 SCV000485170 pathogenic Glycogen storage disease, type II 2015-12-27 criteria provided, single submitter clinical testing
GeneReviews RCV000055768 SCV000086726 pathologic Glycogen storage disease, type II 2013-05-09 no assertion criteria provided curation Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000055768 SCV000919370 pathogenic Glycogen storage disease, type II 2018-02-08 criteria provided, single submitter clinical testing Variant summary: GAA c.1935C>A (p.Asp645Glu) results in a 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 0.00012 in 269490 control chromosomes. c.1935C>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. This variant has been reported to be one of the most common mutations among Chinese patients with Pompe disease, suggesing a founder effect. At least one publication reports experimental evidence evaluating an impact on protein function resulting in 10%-<30% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000055768 SCV000752045 pathogenic Glycogen storage disease, type II 2018-08-10 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 645 of the GAA protein (p.Asp645Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs28940868, ExAC 0.2%). This variant has been reported to be a common cause of glycogen storage disease type II in China, Taiwan and Thailand, although it has also been found in other populations (PMID: 10338092, 21039225, 21232767, 21439876, 21757382, 24269976). ClinVar contains an entry for this variant (Variation ID: 4029). Experimental studies have shown that this missense change reduces GAA enzymatic activity  (PMID: 8094613). A different missense substitution at this codon (p.Asp645Asn) has been determined to be pathogenic (PMID: 9535769, 15145338, 17723315, 20830524). This suggests that the aspartic acid residue is critical for GAA protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004244 SCV000024410 pathogenic Glycogen storage disease type II, infantile 1998-01-01 no assertion criteria provided literature only

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