Evidence Repository - Clinical Genome Resources

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Variant: NM_000152.4(GAA):c.1438-1G>C

CA274472

189184 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2dcfdf9c-a8cc-46b8-a69c-e3dbad873c1c

Approved on: 2020-05-04

Published on: 2020-05-28

HGVS expressions

NM_000152.4:c.1438-1G>C

NM_000152.4(GAA):c.1438-1G>C

NC_000017.11:g.80110726G>C

CM000679.2:g.80110726G>C

NC_000017.10:g.78084525G>C

CM000679.1:g.78084525G>C

NC_000017.9:g.75699120G>C

NG_009822.1:g.14171G>C

NM_000152.3:c.1438-1G>C

NM_001079803.1:c.1438-1G>C

NM_001079804.1:c.1438-1G>C

NM_001079803.2:c.1438-1G>C

NM_001079804.2:c.1438-1G>C

NM_000152.5:c.1438-1G>C

NM_001079803.3:c.1438-1G>C

NM_001079804.3:c.1438-1G>C

ENST00000302262.7:c.1438-1G>C

ENST00000390015.7:c.1438-1G>C

Pathogenic

PM2 PM3 PP4_Moderate PVS1_Strong

Evidence Links 4

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The c.1438-1G>C variant alters the canonical acceptor splice site of intron 9 and is predicted to impact splicing, possibly causing skipping of exon 10 which would result in an in frame deletion that removes ~4% of the primary amino acid sequence, including part of the GAA catalytic barrel (PMIDs 1856189; 22253258; DOI 10.1101/212837). However, in silico splicing predictors indicate the presence of a strong acceptor site 15 nucleotides upstream of the normal site which could be used in the absence of the normal site (Human Splicing Finder score for the normal site is 90.43, and for the upstream site the score is 88.06; MaxEnt Scan score for the normal site is 6.83, and for the upstream site it is 6.94). If the upstream site is used, this would result in the insertion of 5 amino acids and presence of the normal exon 10 sequence. To our knowledge, no functional analysis has been performed to determine the impact of this specific variant. However, the strength of PVS1 has been reduced to PVS1_Strong to recognize impact on the protein suggested by in silico predictors. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00011 in the African population, meeting PM2. Two patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been identified. One patient is compound heterozygous for the variant and c.1655T>C, phase unknown (p.Leu552Pro)(PMIDs 22538254). The second patient was identified in a clinical laboratory and is compound heterozygous for the variant and c.-32-13T>G, phase unknown. This data meets PM3. Pseudodeficiency variants are known to be absent in the second individual and, therefore, PP4_Moderate 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 (PMIDs 27896092, 25455803), or HGVS nomenclature was not used (PMID 24495340). There is a ClinVar entry for this variant (Variation ID: 189184, 2 star review status) for which two submitters classify 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_Strong, PM2, PM3, PP4_Moderate.

PM2

The highest population minor allele frequency in gnomAD is 0.00011 (African) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion.

PM3

Two patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been identified. One patient is compound heterozygous for the variant and c.1655T>C, phase unknown (p.Leu552Pro)(PMIDs 22538254)(0.5 points). The second patient was identified in a clinical laboratory and is compound heterozygous for the variant and c.-32-13T>G. The phase is unknown (0.5 points). A total of 1 point was given, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 27896092, 25455803), or HGVS nomenclature was not used (PMID 24495340).

P18 is compound heterozygous for c.1438-1G>C and c.-32-13T>G (written as c.-45T>G in the article). The phase is unknown. The patient is described as having late-onset Pompe disease but results of GAA enzyme activity were not provided, and therefore this data will not be included (does not meet PP4). PubMed:25455803

PubMed:27896092

PubMed:24495340

PubMed:22538254

PP4_Moderate

One patient has been reported with this variant with GAA activity <1% normal GAA activity in fibroblasts or muscle samples (PMID 22538254), and another patient was identified in a clinical laboratory with deficient activity in dried blood spot. Pseudodeficiency variants are known to be absent in the latter patient and, therefore, PP4_Moderate can be applied.

PVS1_Strong

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