Evidence Repository
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_000152.3(GAA):c.2608C>T (p.Arg870Ter)

CA274250

189009 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 86e9d9c6-29f3-4e4a-b47d-4d300bbeba41
Approved on: 2020-02-14
Published on: 2020-05-26

HGVS expressions

NM_000152.3:c.2608C>T
NM_000152.3(GAA):c.2608C>T (p.Arg870Ter)
NM_001079803.1:c.2608C>T
NM_001079804.1:c.2608C>T
NM_000152.4:c.2608C>T
NM_001079803.2:c.2608C>T
NM_001079804.2:c.2608C>T
NM_000152.5:c.2608C>T
NM_001079803.3:c.2608C>T
NM_001079804.3:c.2608C>T
ENST00000302262.7:c.2608C>T
ENST00000390015.7:c.2608C>T
ENST00000573556.1:n.561C>T
NC_000017.11:g.80118319C>T
CM000679.2:g.80118319C>T
NC_000017.10:g.78092118C>T
CM000679.1:g.78092118C>T
NC_000017.9:g.75706713C>T
NG_009822.1:g.21764C>T

Pathogenic

Met criteria codes 4
PP4 PM2 PM3 PVS1

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
This variant, c.2608C>T (p.Arg870Ter), is a nonsense variant that is expected to result in nonsense mediated decay and absence of gene product. This is supported by the lack of cross reactive immunological material in cultured fibroblasts from a patient with this variant (PMID 22252923). Therefore, PVS1 can be applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting the ClinGen LSD VCEP’s threshold for PM2. This variant has been reported in patients meeting the ClinGen LSD VCEP’s PP4 criterion who also carry a known pathogenic variant in GAA, either c.-32-13T>G or c.525delT, phase unknown (PMIDs 17723315, 26497565), and a patient who is homozygous for the variant (PMID 26497565). Therefore, PP4 and PM3 can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMID 28763149), or a case with the same variant (not confirmed in trans) had already been included (PMID 17056254, 22676651). There is a ClinVar entry for this variant (Variation ID: 189009, 2 star review status) with five submitters classifying the variant as 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, PM2, PM3, PP4.
Met criteria codes
PP4
At least one individual has 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 (PMID 26497565). This meets the criteria for PP4.
Patient 9 is compound heterozygous for c.2608C>T (p.Arg870Ter) and c.-32-13T>G (Pathogenic variant). The phase of the variants is unknown. GAA activity in lymphocytes is 0.03 nmol/min/mg protein (normal range 0.17–0.42); neutral glucosidase was 0.76 (normal range 0.96–1.35), neutral/acid ratio was 25 (normal 2.70–6.80). The normal mean is not provided and therefore, it is not possible to determine whether the residual GAA activity for the patient is <10% normal mean. This data does not meet PP4. PubMed:17056254
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion.
PM3
This variant has been reported in patients meeting the ClinGen LSD VCEP’s PP4 criterion who also carry a known pathogenic variant, either c.-32-13T>G or c.525delT, phase unknown (PMIDs 17723315, 26497565), and a patient who is homozygous for the variant (PMID 26497565) allowing PP4 and PM3 to be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMID 28763149), or a case with the same variant (not confirmed in trans) had already been included (PMID 17056254, 22676651). A total of 1.5 points was awarded, meeting PM3.
Patient 13 is homozygous for c.2608C>T (p.Arg870Ter). No parental testing or GAA activity results are available. Therefore, this data will not be included. PubMed:19588081
Patient 23 (Table 1) is compound heterozygous for c.2608C>T (p.Arg870Ter) and c.-32-13T>G (Pathogenic variant). The phase of the variants is unknown. GAA activity in cultured fibroblasts is 13.2% normal, meeting PP4. 0.5 points. PubMed:17723315
Patient 9 is compound heterozygous for c.2608C>T (p.Arg870Ter) and c.-32-13T>G (Pathogenic variant). The phase of the variants is unknown. GAA activity in lymphocytes is provided but the patient does not meet PP4, and therefore this data will not be included. PubMed:17056254
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. This is supported by cross reactive immunological material studies in cultured fibroblasts (PMID 22252923).
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