Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000152.5(GAA):c.1076-22T>G

CA8815157

370278 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6c34d3ac-52aa-4054-b9e3-ab95609f4ebe

HGVS expressions

NM_000152.5:c.1076-22T>G

NM_000152.5(GAA):c.1076-22T>G

NC_000017.11:g.80108467T>G

CM000679.2:g.80108467T>G

NC_000017.10:g.78082266T>G

CM000679.1:g.78082266T>G

NC_000017.9:g.75696861T>G

NG_009822.1:g.11912T>G

ENST00000570803.6:c.1076-22T>G

ENST00000572080.2:c.1076-22T>G

ENST00000577106.6:c.1076-22T>G

ENST00000302262.8:c.1076-22T>G

ENST00000302262.7:c.1076-22T>G

ENST00000390015.7:c.1076-22T>G

NM_000152.3:c.1076-22T>G

NM_001079803.1:c.1076-22T>G

NM_001079804.1:c.1076-22T>G

NM_000152.4:c.1076-22T>G

NM_001079803.2:c.1076-22T>G

NM_001079804.2:c.1076-22T>G

NM_001079803.3:c.1076-22T>G

NM_001079804.3:c.1076-22T>G

Pathogenic

PVS1_Strong PM2_Supporting PP4_Moderate PM3_Very Strong

PP3

Evidence Links 0

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.1076-22T>G variant in GAA occurs within intron 6. Experimental studies show that the variant causes skipping of biologically-relevant-exon 6 resulting in an in-frame deletion of amino acids 319-358 (PMIDs 9259196, 10737124). This includes part of the GAA catalytic barrel (amino acids 347-727) (Kroos et al, 2012, PMID 22253258; Deming et al, 2017; DOI 10.1101/212837) (PVS1_Strong). At least 7 probands have been reported with this variant, at least 5 of them with reported GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PP4_Moderate). Of these individuals, 6 are compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP, including 2 confirmed in trans - c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (PMID: 9259196), c.1437+1G>A (ClinVar Variation ID: 555864, SCV004227900.1), and 4 with phase unknown - c.1942G>A (p.Gly648Ser) (ClinVar Variation ID: 188902, SCV001371752.2) (PMID: 25455803), c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 22613277), c.1841C>A (p.Thr614Lys) (ClinVar Variation ID: 167113, SCV001371751.1) (PMID: 21484825), and c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (PMID: 29181627). In addition, two siblings are homozygous for the variant (PMID: 10737124) (PM3_VeryStrong). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002658 (3/112848 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 370278). In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PVS1_Strong, PM3_Strong, PP4_Moderate, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on February 6, 2024).

PVS1_Strong

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.00002658 (3/112848 alleles) in the European non-Finnish population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).

PP4_Moderate

At least 5 individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PP4_Moderate).

PM3_Very Strong

This variant has been detected in 6 compound heterozygosity with another variant in GAA that has been classified as pathogenic or likely pathogenic by the ClinGen Lysosomal Diseases VCEP, including 2 confirmed in trans - c.2560C>T (p.Arg854Ter) (ClinVar Variation ID: 4034, SCV001371731.1) (PMID: 9259196) (1 point), c.1437+1G>A (ClinVar Variation ID: 555864, SCV004227900.1) (1 point), and 4 with phase unknown - c.1942G>A (p.Gly648Ser) (ClinVar Variation ID: 188902, SCV001371752.2) (PMID: 25455803) (0.5 points), c.-32-13T>G (ClinVar Variation ID: 4027) (PMID: 22613277) (0.5 points), c.1841C>A (p.Thr614Lys) (ClinVar Variation ID: 167113, SCV001371751.1) (PMID: 21484825) (0.5 points), and c.525delT (ClinVar Variation ID: 4033, SCV001443331.1) (PMID: 29181627) (0.5 points). In addition, two siblings are homozygous for the variant (PMID: 10737124) (0.5 points). Total 4.5 points (PM3_VeryStrong).

PP3

The computational splicing predictor SpliceAI gives a score of 0.56 for acceptor loss and predicts that a new acceptor splice site is created by the variant with a score of 0.97, suggesting that this variant impacts splicing. The impact on splicing is included under PVS1_Strong based on the recommendations of Walker et al (PMID: 37352859).

Approved on: 2024-02-06

Published on: 2024-03-27

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