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_000152.5(GAA):c.2560C>T (p.Arg854Ter)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA340130

4034 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 776f5950-2479-4a1e-8e9a-23242b1a7f2c

Approved on: 2020-05-05

Published on: 2020-05-28

HGVS expressions

NM_000152.5:c.2560C>T

NM_000152.5(GAA):c.2560C>T (p.Arg854Ter)

NC_000017.11:g.80118271C>T

CM000679.2:g.80118271C>T

NC_000017.10:g.78092070C>T

CM000679.1:g.78092070C>T

NC_000017.9:g.75706665C>T

NG_009822.1:g.21716C>T

NM_000152.3:c.2560C>T

NM_001079803.1:c.2560C>T

NM_001079804.1:c.2560C>T

NM_000152.4:c.2560C>T

NM_001079803.2:c.2560C>T

NM_001079804.2:c.2560C>T

NM_001079803.3:c.2560C>T

NM_001079804.3:c.2560C>T

ENST00000302262.7:c.2560C>T

ENST00000390015.7:c.2560C>T

ENST00000573556.1:n.513C>T

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PP4 PVS1 PM3_Very Strong

PM2

Evidence Links 0

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

This variant, c.2560C>T (p.Arg854Ter) is a nonsense variant that is predicted to result in a premature stop codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by reports of numerous patients who are homozygous for the variant, or compound heterozygous for the variant and another loss of function variant, and who have absent GAA cross-reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (e.g. PMIDs 19775921, 21889385, 22237443, 22252923, 23601496, 2574186). In addition, expression of the variant in COS cells resulted in virtually no increase in activity compared to the negative control (PMID 8094613). This variant is the most commonly reported variant in individuals with infantile onset Pompe disease, especially in those of African descent (PMIDs 9529346, 22253258, 31342611). The highest population minor allele frequency is gnomAD v2.1.1 is 0.00189 in the African population. This variant been reported in numerous individuals with Pompe disease who meet the specifications of the ClinGen LSD VCEP for PP4. This includes homozygous individuals (e.g. PMIDs 17723315, 21889385, 23601496, 25741864, 26497565) and compound heterozygotes with another pathogenic variant in GAA such as c.-32-13G>T (PMID 17723315), c.525delT (PMID 23825616), c.1165delG (PMID 22252923), c.1654delC (PMID 25741864), c.1933G>A (p.Asp645Asn) (PMID 31193175), c.1655T>C (p.Leu552Pro)(PMID 31193175). This data meets PM3_Very Strong. 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: PVS1, PM3_Very Strong, PP4.

PP4

Numerous patients have been reported who are homozygous or compound heterozygous for this variant and have 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, meeting PP4. Also note that homozygous individuals have been repeatedly shown to be CRIM-negative, as are individuals who are compound heterozygous for c.2560C>T (p.Arg854Ter) and another loss of function variant (PMIDs 8094613, 16860134, 22237443, 23601496, 26497565). Note that many additional examples are available in the literature but PP4 has already been met.

PVS1

This variant is predicted to result in a premature stop codon resulting in nonsense mediated decay and lack of gene product. This is supported by reports of numerous patients who are homozygous for the variant, or compound heterozygous for the variant and another loss of function variant, and who have absent GAA cross reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (e.g. PMIDs 19775921, 21889385, 22237443, 22252923, 23601496, 2574186). In addition, expression of the variant in COS cells resulted in virtually no increase in activity compared to the negative control (PMID 8094613).

PM3_Very Strong

It been reported in numerous individuals who meet PP4 specifications including homozygous individuals (e.g. PMIDs 17723315, 21889385, 23601496, 25741864, 26497565; 1 point max) and compound heterozygotes with another pathogenic variant in GAA such as c.-32-13G>T (PMID 17723315; 0.5 points), c.525delT (PMID 23825616; 0.5 points), c.1165delG (PMID 22252923; 0.5 points), c.1654delC (PMID 25741864; 0.5 points), c.1933G>A (p.Asp645Asn) (PMID 31193175; 0.5 points), c.1655T>C (p.Leu552Pro)(PMID 31193175; 0.5 points). This data was given a total of 4 points based on the guidelines of the ClinGen LSD VCEP. Further examples are available in the literature but PM3_Very Strong has already been met.

PM2

This variant has a highest population minor allele frequency in gnomAD v2.1.1 of 0.00189 in Africans. This is higher than the ClinGen LSD VCEP's threshold for PM2 (<0.001), which is a conservative threshold. Additional evidence will be assessed support the pathogenicity of this variant.

Curation History

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