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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000152.5(GAA):c.1722C>T (p.Leu574=)

CA239730

193975 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 35dce1d2-1402-42d8-a0ea-bb2fd7bc225f
Approved on: 2024-09-03
Published on: 2024-09-03

HGVS expressions

NM_000152.5:c.1722C>T
NM_000152.5(GAA):c.1722C>T (p.Leu574=)
NC_000017.11:g.80112068C>T
CM000679.2:g.80112068C>T
NC_000017.10:g.78085867C>T
CM000679.1:g.78085867C>T
NC_000017.9:g.75700462C>T
NG_009822.1:g.15513C>T
ENST00000570803.6:c.1722C>T
ENST00000572080.2:c.1722C>T
ENST00000577106.6:c.1722C>T
ENST00000302262.8:c.1722C>T
ENST00000302262.7:c.1722C>T
ENST00000390015.7:c.1722C>T
ENST00000572080.1:c.110C>T
ENST00000572803.1:n.336C>T
NM_000152.3:c.1722C>T
NM_001079803.1:c.1722C>T
NM_001079804.1:c.1722C>T
NM_000152.4:c.1722C>T
NM_001079803.2:c.1722C>T
NM_001079804.2:c.1722C>T
NM_001079803.3:c.1722C>T
NM_001079804.3:c.1722C>T
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Uncertain Significance

Met criteria codes 2
BP4 PM2_Supporting
Not Met criteria codes 1
BP7

Evidence Links 0

Expert Panel

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.1722C>T (p.Leu574=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. However, it occurs at a nucleotide that is conserved as shown by PhyloP score of 0.218, so BP7 cannot be applied. The highest population minor allele frequency in gnomAD v4.10. is 0.0006477 (59/91092 alleles) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). It has not been reported in any individuals with Pompe disease to our knowledge. There is a ClinVar entry for this variant (Variation ID: 193975). Due to conflicting evidence, this variant is classified as a variant of unknown significance for Pompe disease based on the GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert Panel (Specifications Version 2.0): PM2_supporting, BP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on September 3, 2024)
Met criteria codes
BP4
The computational splicing predictor SpliceAI gives a score of 0.05 for acceptor loss suggesting that the variant has no impact on splicing (BP4).
PM2_Supporting
The highest population minor allele frequency in gnomAD v4.10. is 0.0006477 (59/91092 alleles; 1 homozygote) in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).
Not Met criteria codes
BP7
The NM_000152.5:c.1722C>T (p.Leu574=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. However, it occurs at a nucleotide that is conserved as shown by PhyloP score of 0.218, so BP7 cannot be applied.
Curation History
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