Variant: NM_000152.4(GAA):c.2815_2816delGT (p.Val939Leufs)

x This classification has been retracted/unpublished!

CA8815886

371481 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 64e55556-7d65-4dec-a132-6c99d5049dc5

Approved on: 2021-10-26

Published on: 2021-11-19

HGVS expressions

NM_000152.4:c.2815_2816delGT
NM_000152.4(GAA):c.2815_2816delGT (p.Val939Leufs)
NC_000017.11:g.80119287_80119288del
CM000679.2:g.80119287_80119288del
NC_000017.10:g.78093086_78093087del
CM000679.1:g.78093086_78093087del
NC_000017.9:g.75707681_75707682del
NG_009822.1:g.22732_22733del
ENST00000570803.6:c.2815_2816del
ENST00000572080.2:c.*953_*954del
ENST00000577106.6:c.2815_2816del
ENST00000302262.8:c.2815_2816del
ENST00000302262.7:c.2815_2816del
ENST00000390015.7:c.2815_2816del
NM_000152.3:c.2815_2816del
NM_001079803.1:c.2815_2816del
NM_001079804.1:c.2815_2816del
NM_000152.4:c.2815_2816del
NM_001079803.2:c.2815_2816del
NM_001079804.2:c.2815_2816del
NM_000152.5:c.2815_2816del
NM_001079803.3:c.2815_2816del
NM_001079804.3:c.2815_2816del

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM3_Strong PVS1_Moderate PP4_Moderate

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5: c.2815_2816del (p.Val939LeufsTer78) variant in GAA is a frameshift variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. The frameshift begins at amino acid 939; the normal GAA gene product is 952 amino acids in length. Hence <10% of the normal product is missing. The impact of adding an abnormal sequence of 78 amino acids to the C terminus of GAA, due to the frameshift, is unknown (PVS1_Moderate). At least 8 patients with this variant who have been diagnosed with Pompe disease have been described including 2 patients for whom residual GAA activity was provided and was either <1% normal in cultured skin fibroblasts (PMID 22538254) or below the normal range in dried blood spots (https://doi.org/10.3390/metabo11070446). One of these patients and at least 2 additional patients were on enzyme replacement therapy (PMID 22538254, 25316892, 32373469, https://www.neurology-asia.org/articles/neuroasia-2021-26(2)-413.pdf) (PP4_Moderate). Of the reported patients, one is compound heterozygous for c.118C>T (p.Arg40Ter) (PMID 24269976, ClinVar SCV SCV001371737.1), and at least two patients are compound heterozygous for the variant and c.1935C>A (p.Asp645Glu) (PMID 32373469, in trans; PMID 28394184, 22538254, phase unknown)(PM3_Strong). Additional patients have been reported as compound heterozygous for the variant and c.2585delG (PMID 28394184), c.2238G>C (p.Trp746Cys) (PMID 25316892) and c.266G>T (p.Arg89Leu) (https://doi.org/10.3390/metabo11070446). The in trans data from these patients will be used for the assessment of the other variant and is not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001631 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 371481, 2 star review status) with 2 submitters classifying the variant as pathogenic and one as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel (ACMG/AMP specifications version 2.0): PM3_Strong, PVS1_Moderate, PP4_Moderate, PM2_Supporting (Classification approved by the ClinGen LSD VCEP - Oct.19.2021)

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001631 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting).
• PM3_Strong: At least 7 patients with this variant who have been diagnosed with Pompe disease have been described. One of these patients is compound heterozygous for c.118C>T (p.Arg40Ter) (PMID 24269976, ClinVar SCV SCV001371737.1, 0.5 points), and at least two patients are compound heterozygous for c.1935C>A (p.Asp645Glu) (PMID 32373469, in trans, 1 point; PMID 28394184, 22538254, phase unknown, 0.5 points). Total 2 points for PM3 (PM3_Strong). Additional patients have been reported as compound heterozygous for the variant and c.2585delG (PMID 28394184), c.2238G>C (p.Trp746Cys) (PMID 25316892) and c.266G>T (p.Arg89Leu) (https://doi.org/10.3390/metabo11070446). The in trans data from these patients will be used for the assessment of the other variant and is not included here in order to avoid circular logic.
• PVS1_Moderate: The NM_000152.5: c.2815_2816del (p.Val939LeufsTer78) variant in GAA is a frameshift variant predicted to cause a premature stop codon in the last exon of the gene and therefore to escape nonsense mediated decay. The frameshift begins at amino acid 939; the normal GAA gene product is 952 amino acids in length. Hence <10% of the normal product is missing. The impact of adding an abnormal sequence of 78 amino acids to the C terminus of GAA, due to the frameshift, is unknown (PVS1_Moderate).
• PP4_Moderate: At least 7 patients with this variant who have been diagnosed with Pompe disease have been described including 2 patients for whom residual GAA activity was provided and was either <1% normal in cultured skin fibroblasts (PMID 22538254) or below the normal range in dried blood spots (https://doi.org/10.3390/metabo11070446). One of these patients and at least 2 additional patients were on enzyme replacement therapy (PMID 22538254, 25316892, 32373469, https://www.neurology-asia.org/articles/neuroasia-2021-26(2)-413.pdf) (PP4_Moderate).