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]

Variant: NM_000152.4(GAA):c.1128_1129delGGinsC (p.Trp376Cysfs)

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CA274311

189041 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 9158564f-80b6-4c7a-82de-d3e89e0d76a9

Approved on: 2020-02-14

Published on: 2020-05-26

HGVS expressions

NM_000152.4:c.1128_1129delGGinsC

NM_000152.4(GAA):c.1128_1129delGGinsC (p.Trp376Cysfs)

NC_000017.11:g.80108541_80108542delinsC

CM000679.2:g.80108541_80108542delinsC

NC_000017.10:g.78082340_78082341delinsC

CM000679.1:g.78082340_78082341delinsC

NC_000017.9:g.75696935_75696936delinsC

NG_009822.1:g.11986_11987delinsC

NM_000152.3:c.1128_1129delinsC

NM_001079803.1:c.1128_1129delinsC

NM_001079804.1:c.1128_1129delinsC

NM_000152.4:c.1128_1129delinsC

NM_001079803.2:c.1128_1129delinsC

NM_001079804.2:c.1128_1129delinsC

NM_000152.5:c.1128_1129delinsC

NM_001079803.3:c.1128_1129delinsC

NM_001079804.3:c.1128_1129delinsC

ENST00000302262.7:c.1128_1129delinsC

ENST00000390015.7:c.1128_1129delinsC

Pathogenic

PVS1 PP4 PM2 PM3

Evidence Links 6

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.1128_1129delGGinsC (p.Trp376Cysfs), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. Two individuals have been reported who meet the ClinGen LSD VCEP’s specifications for PP4 and who are compound heterozygous for c.1128_1129delGGinsC (p.Trp376Cysfs) and a unique pathogenic variant in GAA; one individual has infantile-onset Pompe disease and is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter), phase unknown (PMID 22237443), the second individual has late onset Pompe disease and is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 26873529). Based on this data, PM3 can be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 29523196, 27408821), full HGVS nomenclature was not provided (PMID 20033296), or the second variant is a variant of unknown significance (PMID 18607768). There is a ClinVar entry for this variant (Variation ID: 189041, 2 star review status) with 3 submitters classifying the variant and pathogenic and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM3, PM2, PP4.

PVS1

This variant is predicted to result in a premature stop codon that is detected by nonsense mediated decay resulting in lack of gene product.

PP4

Two individuals have been reported that meet PP4 specifications; one with "absent" GAA activity and one with leukocyte activity in the affected range (PMIDs 22237443, 26873529).

Patient 2 has "absent" GAA activity (see Table 1), meeting PP4; tissue type not stated. PubMed:22237443

PM2

This variant is absent in gnomAD v2.1.1.

PM3

Two individuals have been reported who meet the ClinGen LSD VCEP’s specifications for PP4 and who are compound heterozygous for c.1128_1129delGGinsC (p.Trp376Cysfs) and a unique pathogenic variant in GAA; one individual has infantile-onset Pompe disease and is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter), phase unknown (PMID: 22237443), the second individual has late onset Pompe disease and is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 26873529). Based on this data, PM3 can be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 29523196, 27408821), full HGVS nomenclature was not provided (PMID 20033296), or the second variant is a variant of unknown significance (PMID 18607768).

c.1128_1129delGGinsC was found in compound heterozygosity with a pathogenic variant, c.2237G>A (p.Trp746Ter), in an individual with infantile onset Pompe disease and "absent" GAA activity. c.2237G>A (p.Trp746Ter) has been classified as pathogenic by multiple ClinVar submitters and by the ClinGen LSd VCEP (note that c.2237G>A can be classified as pathogenic without including data for c.1128_1129delGGinsC, thus avoiding a circular argument). The phase of the variants is unknown in this patient. Based on the ClinGen LSD VCEP guidelines for assessing strength of evidence for PM3, 0.5 points were awarded. PubMed:22237443

c.1128_1129delGGinsC was found in compound heterozygosity with a pathogenic variant, -32-13T>G (a known pathogenic variant), in an individual with late onset Pompe disease. The phase is unknown. No GAA activity data is available, and therefore this data will not be included. PubMed:27408821

p.Trp376Cysfs was found in compound heterozygosity with p.Gly219Arg. This data was not counted because the cDNA changes for the variants were not provided. PubMed:20033296

c.1128_1129delGGinsC was found in compound heterozygosity with a pathogenic variant, -32-13T>G, in an individual with late onset Pompe disease. The phase is unknown. No GAA activity data is available,and therefore this data will not be included. The patient is on ERT. PubMed:29523196

PubMed:26873529

c.1128_1129delGGinsC was found in compound heterozygosity with c.885C>G (p.His295Gln), a variant of unknown significance, in an individual with late onset Pompe disease and GAA activity <30% of lower normal range in muscle. The phase of the variants is unknown. No points are given because the second variant is a variant of unknown significance and the patient does not meet PP4 criteria. PubMed:18607768

Curation History

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