Variant: NM_000152.5(GAA):c.1826dup (p.Tyr609Terfs)

CA274414

189144 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: f17c6338-2255-4ce6-93e0-2e1565023eec

HGVS expressions

NM_000152.5:c.1826dup
NM_000152.5(GAA):c.1826dup (p.Tyr609Terfs)
NM_000152.3:c.1826dup
NM_001079803.1:c.1826dup
NM_001079804.1:c.1826dup
NM_000152.4:c.1826dup
NM_001079803.2:c.1826dup
NM_001079804.2:c.1826dup
NM_001079803.3:c.1826dup
NM_001079804.3:c.1826dup
ENST00000302262.7:c.1826dup
ENST00000390015.7:c.1826dup
ENST00000570716.1:n.266dup
ENST00000572080.1:n.214dup
ENST00000572803.1:n.440dup
NC_000017.11:g.80112649dup
CM000679.2:g.80112649dup
NC_000017.10:g.78086448dup
CM000679.1:g.78086448dup
NC_000017.9:g.75701043dup
NG_009822.1:g.16094dup

Pathogenic

• Met criteria codes: PM3 PM2 PVS1 PP4

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.1826dup (p.Tyr609Terfs), is predicted to cause a frameshift, premature termination codon, and nonsense mediated decay resulting in lack of gene product. This is supported by the absence of cross-reactive immunological material in cultured fibroblasts from a patient with the variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001816 in the European non-Finnish population, meeting PM2. Two individuals meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported who are compound heterozygous for the variant and a unique pathogenic variant; one of these patients is compound heterozygous for the variant and c.525delT, and the other patient is compound heterozygous for the variant and c.2238G>A (p.Trp746Ter) (PMIDs 12897283, 25741864). Therefore, PP4 and PM3 can be applied. Another patient was reported who is compound heterozygous for this variant and a known pathogenic variant (c.525delT), but this data was not included because the GAA activity for the patient was not reported (PMID 14695532). In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PM3, PP4.

Met criteria codes

• PM3: This variant was found in compound heterozygosity with a unique pathogenic variant in GAA in 2 patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 specifications (PMIDs 12897283, 25741864). The phase of the variants is unknown. Based on the ClinGen LSD VCEP's specifications, this data was given a total of 1 point, meeting PM3. Another patient was reported who is compound heterozygous for this variant and a known pathogenic variant (c.525delT), but this data was not included because the GAA activity for the patient was not reported (PMID 14695532).
• PM2: The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001816 (European non-Finnish), which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion.
• PVS1: This is a frameshift variant which is predicted to result in a premature termination codon and nonsense mediated decay resulting in no gene product. This is supported by the report that c.1826dup is a CRIM-negative allele (PMID 22252923).
• PP4: Two individuals have been reported with this variant and GAA activity <10% normal in fibroblast and/or muscle samples (PMIDs 12897283, 25741864) meeting the ClinGen LSD VCEP's specifications for PP4.

Approved on: 2020-02-14

Published on: 2020-05-27