Variant: NM_000152.5(GAA):c.437del (p.Met146fs)

CA658824775

554096 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: ad8f9e43-3049-4820-8f7a-9b1c912ed389

HGVS expressions

NM_000152.5:c.437del
NM_000152.5(GAA):c.437del (p.Met146fs)
NC_000017.11:g.80105023del
CM000679.2:g.80105023del
NC_000017.10:g.78078822del
CM000679.1:g.78078822del
NC_000017.9:g.75693417del
NG_009822.1:g.8468del
ENST00000302262.8:c.437del
ENST00000302262.7:c.437del
ENST00000390015.7:c.437del
ENST00000570803.5:c.437del
ENST00000577106.5:c.437del
NM_000152.3:c.437del
NM_001079803.1:c.437del
NM_001079804.1:c.437del
NM_000152.4:c.437del
NM_001079803.2:c.437del
NM_001079804.2:c.437del
NM_001079803.3:c.437del
NM_001079804.3:c.437del

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PM3_Supporting PP4_Moderate

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.437del (p.Met146ArgfsTer7) variant in GAA is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The variant was found in compound heterozygosity with a pathogenic variant in two patients who meet the ClinGen LSD VCEP's PP4 specifications; one with c.2237G>A (p.Trp746Ter) (PMID 26693141), and the other with c.2481+102_2646+31del (PMID 22658377)(PP4_Moderate, PM3_Supporting). There is a ClinVar entry for this variant (Variation ID: 554096, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP (specification version 2.0): PVS1, PM2_Supporting, PM3_Supporting, PP4_Moderate.

Met criteria codes

• PM2_Supporting: This variant is absent in gnomAD, meeting PM2_Supporting.
• PVS1: This is a frameshift variant which is predicted to result in a premature termination codon, nonsense mediated decay, and lack gene product. Therefore, PVS1 can be applied. Furthermore, and individual who was compound heterozygous for the variant and another loss of function variant had no GAA cross reactive immunological material in cultured skin fibroblasts (PMID 26693141) supporting that c.437del results in lack of gene product.
• PM3_Supporting: This variant has been detected in at least 2 individuals with Pompe disease. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (p.Trp746X, PMID: 26693141, 0.5 pt) (PM3_Supporting).
• PP4_Moderate: At least 2 patient(s) with this variant had documented GAA deficiency with <10% of normal mean control level of GAA activity in leukocytes, lymphocytes, muscle samples, or were reported to be on enzyme replacement therapy for Pompe disease (PP4_Moderate).

Approved on: 2021-08-24

Published on: 2021-09-28