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]

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Variant: NM_001079804.3:c.2456G>C

CA401325305

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b9e5a45b-ca59-4eae-888f-d21b7f925693

Approved on: 2022-06-30

Published on: 2022-06-30

HGVS expressions

NM_001079804.3:c.2456G>C

NC_000017.11:g.80117724G>C

CM000679.2:g.80117724G>C

NC_000017.10:g.78091523G>C

CM000679.1:g.78091523G>C

NC_000017.9:g.75706118G>C

NG_009822.1:g.21169G>C

ENST00000302262.8:c.2456G>C

ENST00000302262.7:c.2456G>C

ENST00000390015.7:c.2456G>C

ENST00000573556.1:n.409G>C

NM_000152.3:c.2456G>C

NM_001079803.1:c.2456G>C

NM_001079804.1:c.2456G>C

NM_000152.4:c.2456G>C

NM_001079803.2:c.2456G>C

NM_001079804.2:c.2456G>C

NM_000152.5:c.2456G>C

NM_001079803.3:c.2456G>C

Likely Pathogenic

PP3 PM5_Supporting PM3 PP4_Moderate PS3_Moderate PM2_Supporting

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(GAA):c.2456G>C variant in GAA is a missense variant predicted to cause substitution of arginine by proline at amino acid 819 (p.Arg819Pro). This variant has been detected in at least 6 individuals with Pompe disease (PMID: 22644586, 22252923, 30214072) with deficient GAA activity. Of those individuals, one was compound heterozygous for the variant and a pathogenic variant and one was homozygous for the variant (PMID: 30214072, internal lab data), meeting PP4_Moderate and PM3. It is absent in gnomAD, meeting PM2. Functional assays support a deleterious effect of this variant, when expressed in COS cells, this variant was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID:22644586). This includes 0.4% GAA activity in cells and 2.0% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3_Moderate. Computational evidence also supports a deleterious effect; REVEL score = 0.926 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion. Another missense variant [c.2455C>T, p.Arg819Trp] [ClinVar Variation ID:456402] in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting). There is no Clinvar entry for this variant. In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. ACMG/AMP criteria met, based on the specification of the ClinGen LSD VCEP: PP4_Moderate, PM3, PS3_Moderate, PP3, PM2_Supporting, and PM5_Supporting.

PP3

REVEL score = 0.926 which is higher than the LSD VCEP threshold for PP3 (>0.7) and therefore meets this criterion.

PM5_Supporting

Another missense variant [c.2455C>T, p.Arg819Trp] [ClinVar Variation ID:456402] in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen LSD VCEP (PM5_Supporting).

PM3

This variant has been detected in at least 6 individuals with Pompe disease (PMID: 22644586, 22252923, 30214072). Of those individuals, one was compound heterozygous for the variant and a pathogenic variant and two were homozygous for the variant (PMID: 30214072, internal lab data). 1.5 point awarded for PM3

PP4_Moderate

The variant was seen in patients (PMID: 22644586, 22252923, 30214072) with deficient GAA activity but results were not provided and reported to be on enzyme replacement therapy (PMID: 30214072). This meets the criteria for PP4_Moderate

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 0.4% GAA activity in cells and 2.0% in medium, and evidence of abnormal synthesis and processing on Western blot. This meets the ClinGen LSD VCEP specifications for PS3_Moderate.

PM2_Supporting

This variant is absent in gnomAD, meeting PM2_Supporting.

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