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_000152.4(GAA):c.1064T>C (p.Leu355Pro)

Curation Version - 1.4
Curation History
JSON LD for Version 1.4

CA8815136

284093 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7b23f882-c6fd-4d3b-b9ef-d2268a89f53a

Approved on: 2021-09-07

Published on: 2021-09-07

HGVS expressions

NM_000152.4:c.1064T>C

NM_000152.4(GAA):c.1064T>C (p.Leu355Pro)

NC_000017.11:g.80108398T>C

CM000679.2:g.80108398T>C

NC_000017.10:g.78082197T>C

CM000679.1:g.78082197T>C

NC_000017.9:g.75696792T>C

NG_009822.1:g.11843T>C

ENST00000302262.8:c.1064T>C

ENST00000302262.7:c.1064T>C

ENST00000390015.7:c.1064T>C

NM_000152.3:c.1064T>C

NM_001079803.1:c.1064T>C

NM_001079804.1:c.1064T>C

NM_001079803.2:c.1064T>C

NM_001079804.2:c.1064T>C

NM_000152.5:c.1064T>C

NM_001079803.3:c.1064T>C

NM_001079804.3:c.1064T>C

Pathogenic

PP4_Moderate PM2_Supporting PP3 PS3_Moderate PM3_Strong

PM5 PS1

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.1064T>C variant in GAA is a missense variant predicted to cause substitution of leucine to proline at amino acid 355 (p.Leu355Pro). This variant has been reported in over 20 individuals with Pompe disease including at least 9 individuals with documented laboratory values showing GAA deficiency (PP4_Moderate) (PMIDs 14972326, 17213836, 17723315, 17213836, 23632174, 24016645, 30595407)(PP4_Moderate). The variant is homozygous in multiple patients (PMIDs 14972326, 16917947, 17213836, 17573812, 17723315, 18429042, 22658377, 23787031, 24016645, 30023291, 33325062). Three individuals are compound heterozygous for the variant and another variant that has been assessed as pathogenic by the ClinGen LSD VCEP; c.-32-13T>G in two patients (PMIDs 17643989, 21803581), and confirmed in trans with c.670C>T (p.Arg224Trp) in another patient (PMID 23632174; (PM3_Strong). p.Leu355Pro has also been reported in individuals with Pompe disease who are compound heterozygous for c.2041-2A>C (PMID 33325062), c.2303C>G (p.Pro768Arg) (PMID 17027861), c.1210G>A (p.Asp404Asn) (PMID 22658377, 23787031), c.1120T>C (p.Cys374Arg) (PMID 14695532), c.1927G>A (p.Gly643Arg) (PMID 18429042), c.1106T >C (p.Leu369Pro) (PMID 23430493), and c.380G>T (p.Cys127Phe) (PMID 24016645). The in trans data from these patients will be used in the assessment of the other variant and was not included here in order to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/34580) in the Latino population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant results in absent GAA activity, and there is evidence of abnormal synthesis and processing of GAA on Western blot (PMIDs 14695532, 14972326, 19862843) (PS3_Moderate). The computational predictor REVEL gives a score of 0.805 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 284093, 2 star review status) with four submitters each classifying the variant as 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 (Specifications Version 2.0): PM3_Strong, PS3_Moderate, PP4_Moderate, PP3, PM2_Supporting. (Classification approved August 17, 2021)

PP4_Moderate

Over 20 individuals with this variant have been reported to have Pompe disease. At least 9 of these individuals have documented values showing GAA deficiency (PP4_Moderate) (PMIDs 14972326, 17213836, 17723315, 17213836, 23632174, 24016645, 30595407). The variant has also been reported in additional patients with Pompe disease (PMIDs 14695532, 16917947, 17027861, 18429042, 17573812, 17643989, 21803581, 22658377, 23787031, 30023291, 33325062).

PM2_Supporting

The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 (1/34580) in the Latino/Admixed American population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting).

PP3

REVEL (in silico meta predictor for missense changes) score = 0.805 which is higher than the LSD VCEP threshold for PP3, and therefore meets this criterion.

PS3_Moderate

When expressed in COS cells, this variant results in very low (<2% wild type GAA) activity, and there is evidence of abnormal synthesis and processing of GAA on Western blot (PMIDs 14695532, 14972326, 19862843). The meets the specifications for PS3_Moderate.

PM3_Strong

The variant has been reported to be homozygous in multiple patients (1 point) (PMIDs 14972326, 16917947, 17213836, 17573812, 17723315, 18429042, 22658377, 23787031, 24016645, 30023291, 33325062), compound heterozygous with c.-32-13T>G in two patients (PMIDs 17643989, 21803581, 2 X 0.5 points), and confirmed in trans with c.670C>T (p.Arg224Trp) (PMID 23632174; p.Arg224Trp is pathogenic for Pompe disease based on the assessment of the ClinGen LSD VCEP; 1 point). p.Leu355Pro has also been reported in individuals with Pompe disease who are compound heterozygous for c.2041-2A>C (PMID 33325062), c.2303C>G (p.Pro768Arg) (PMID 17027861), c.1210G>A (p.Asp404Asn) (PMID 22658377, 23787031), c.1120T>C (p.Cys374Arg) (PMID 14695532), c.1927G>A (p.Gly643Arg) (PMID 18429042), c.1106T >C (p.Leu369Pro) (PMID 23430493), and c.380G>T (p.Cys127Phe) (PMID 24016645). The in trans data from these patients will be used in the assessment of the other variant and was not included here in order to avoid circular logic. In total, 3 points were given towards PM3, meeting PM3_Strong.

PM5

No other variants at this codon were identified.

PS1

No other variants at this codon were identified.

Curation History

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