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_001079804.3:c.872T>C

CA401363854

Gene: GAA (HGNC:2548)

Condition: glycogen storage disease II (MONDO:0009290)

Inheritance Mode: Autosomal recessive inheritance

UUID: 6f3a7b01-e825-4e59-bd44-f2aaa013e512

Approved on: 2021-12-02

Published on: 2021-12-02

HGVS expressions

NM_001079804.3:c.872T>C

NC_000017.11:g.80107813T>C

CM000679.2:g.80107813T>C

NC_000017.10:g.78081612T>C

CM000679.1:g.78081612T>C

NC_000017.9:g.75696207T>C

NG_009822.1:g.11258T>C

ENST00000302262.8:c.872T>C

ENST00000302262.7:c.872T>C

ENST00000390015.7:c.872T>C

NM_000152.3:c.872T>C

NM_001079803.1:c.872T>C

NM_001079804.1:c.872T>C

NM_000152.4:c.872T>C

NM_001079803.2:c.872T>C

NM_001079804.2:c.872T>C

NM_000152.5:c.872T>C

NM_001079803.3:c.872T>C

Pathogenic

PP4_Moderate PM3_Strong PP3 PS3_Moderate PM2_Supporting

PM5

Evidence Links 0

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.872T>C variant in GAA is a missense variant predicted to cause substitution of leucine by proline at amino acid 291 (p.Leu291Pro). At least 5 patients have been reported with this variant and features consistent with Pompe disease, including documented laboratory values showing deficiency GAA activity and/or treated with enzyme replacement therapy, and/or features consistent with infantile onset Pompe disease meeting specifications of the ClinGen LSD VCEP for PP4_Moderate (PMID 17151339, 18458862, 22353292, 22658377, 24243590, 25213570, 31193175). Additional patients have also been reported (PMID 18425781, 18458862, 29095275). Four patients are compound heterozygous for the variant and GAA variant classified as pathogenic by the ClinGen LSD VCEP, phase unknown, including c.1411_1414del (PMID 24243590; ClinVar SCV001443324.1), c.1798C>T (p.Arg600Cys)(PMID 18458862, 22353292, 25213570; 2 patients), and c.1935C>A (p.Asp645Glu)(PMID 29095275), and at least 2 patients are homozygous for the variant (PMID 16857770, 17151339, 18458862, 22658377, 31193175)(PM3_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). When expressed in COS cells, this variant had 0.7% wild type GAA activity in cells and showed evidence of abnormal synthesis and processing on Western blot (PMID:22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.908 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Two other variants have been identified at the same amino acid position, c.871C>T (p.Leu291Phe) and c.872T>A (p.Leu291His). The data from this variant, c.872T>C (p.Leu291Pro), will be used in the classification of p.Leu291Phe and p.Leu291His and is not included here to avoid circular logic. There is no entry for this variant in ClinVar. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PS3_Moderate, PM3_Strong, PM2_Supporting, PP3, PP4_Moderate.

PP4_Moderate

At least 5 patients have been reported with this variant and features consistent with Pompe disease, including documented laboratory values showing deficiency GAA activity and/or treated with enzyme replacement therapy, and/or features consistent with infantile onset Pompe disease meeting specifications of the ClinGen LSD VCEP for PP4_Moderate (PMID 17151339, 18458862, 22353292, 22658377, 24243590, 25213570, 31193175). Additional patients have also been reported (PMID 18425781, 18458862, 29095275).

PM3_Strong

Four patients with Pompe disease are compound heterozygous for the variant and GAA variant classified as pathogenic by the ClinGen LSD VCEP, phase unknown, including c.1411_1414del (PMID 24243590; ClinVar SCV001443324.1; 0.5 points), c.1798C>T (p.Arg600Cys)(PMID 18458862, 22353292, 25213570; 2 x 0.5 points), and c.1935 C>A (p.Asp645Glu)(PMID 29095275; 0.5 points), and at least 2 patients are homozygous for the variant (PMID 16857770, 17151339, 18458862, 22658377, 31193175; 2 x 0.5 points). Total 3 points (PM3_Strong).

PP3

The computational predictor REVEL gives a score of 0.908 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3)

PS3_Moderate

When expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.7% GAA activity in cells and 1.4% in medium, and evidence of abnormal synthesis and processing on Western blot (PS3_Moderate).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

PM5

Two other variants have been identfied at the same amino acid position, c.871C>T (p.Leu291Phe) and c.872T>A (p.Leu291His). The data from this variant, c.872T>C (p.Leu291Pro), will be used in the classification of p.Leu291Phe and p.Leu291His and is not included here to avoid circular logic.

Curation History

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