ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1441T>C (p.Trp481Arg) (rs772883420)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169391 SCV000220783 likely pathogenic Glycogen storage disease, type II 2014-10-10 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169391 SCV000919383 pathogenic Glycogen storage disease, type II 2018-06-22 criteria provided, single submitter clinical testing Variant summary: GAA c.1441T>C (p.Trp481Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 276888 control chromosomes. c.1441T>C has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease), with reported severely deficient GAA enzyme activity (Tsai_2017, Hermans_2004, Herzog_2012, Raben_1998, van Capelle2016). These data indicate that the variant is likely to be associated with disease. 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.
Invitae RCV000169391 SCV000956690 pathogenic Glycogen storage disease, type II 2018-10-02 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 481 of the GAA protein (p.Trp481Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs772883420, ExAC 0.002%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Pompe disease (PMID: 18757064, Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant has also been reported in combination with another GAA variant in individuals affected with Pompe disease (PMID: 10189220, 14695532, 22676651). ClinVar contains an entry for this variant (Variation ID: 189007). Experimental studies have shown that this missense change results in a GAA protein with residual enzyme activity (PMID: 14695532, 19862843). For these reasons, this variant has been classified as Pathogenic.

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