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.1352C>G (p.Pro451Arg)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA8815294

281330 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b11d7715-7a62-4071-9760-f92fefa72998

Approved on: 2023-05-26

Published on: 2023-05-26

HGVS expressions

NM_000152.5:c.1352C>G

NM_000152.5(GAA):c.1352C>G (p.Pro451Arg)

NC_000017.11:g.80109970C>G

CM000679.2:g.80109970C>G

NC_000017.10:g.78083769C>G

CM000679.1:g.78083769C>G

NC_000017.9:g.75698364C>G

NG_009822.1:g.13415C>G

ENST00000570803.6:c.1352C>G

ENST00000572080.2:c.1352C>G

ENST00000577106.6:c.1352C>G

ENST00000302262.8:c.1352C>G

ENST00000302262.7:c.1352C>G

ENST00000390015.7:c.1352C>G

NM_000152.3:c.1352C>G

NM_001079803.1:c.1352C>G

NM_001079804.1:c.1352C>G

NM_000152.4:c.1352C>G

NM_001079803.2:c.1352C>G

NM_001079804.2:c.1352C>G

NM_001079803.3:c.1352C>G

NM_001079804.3:c.1352C>G

Likely Benign

BS1 BP4

PM3 PP4

Evidence Links 1

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.1352C>G variant in GAA is a missense variant predicted to result in the substitution of proline by arginine at amino acid 451 (p.Pro451Arg). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00488 (121/24796 alleles, including 2 homozygotes) in the African/African-American population. This allele frequency meets the ClinGen LD VCEP threshold (>0.005) for BS1 (after rounding up). The variant was reported in a patient with limb-girdle muscle weakness but was not thought to be causative of the symptoms (PMID: 29149851). The computational predictor REVEL gives a score of 0.449 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function, and SpliceAI predicts no impact on splicing (BP4).There is a ClinVar entry for this variant (Variation ID: 281330). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BS1, BP4. (Classification approved by the ClinGen Lysosomal Diseases VCEP on May 26, 2023)

BS1

The highest population minor allele frequency in gnomAD v2.1.1 is 0.00488 (121/24796 alleles, including 2 homozygotes) in the African/African-American population. This allele frequency meets the ClinGen LD VCEP threshold (>0.005) for BS1 (after rounding up).

BP4

The computational predictor REVEL gives a score of 0.449 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function, and SpliceAI predicts no impact on splicing (BP4).

PM3

A patient with limb-girdle muscle weakness has been reported to be compound heterozygous for c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT (PMID 29149851). The phase of the variants is unknown and no GAA activity was provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype. Therefore, this criterion is not met.

Patient 21, with limb girdle muscular dystrophy, is compound heterozygous for c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT. The phase of the variants is unknown. No GAA activity is provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype. PubMed:29149851

PP4

A patient with limb-girdle muscular dystrophy has been reported to be compound heterozygous for c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT (PMID 29149851). No GAA activity was provided for the patient. Therefore, this criterion is not met.

Patient 21, with limb girdle muscular dystrophy, is compound heterozygous for c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT. No GAA activity is provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype. PubMed:29149851

Curation History

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