Variant: NM_000152.5(GAA):c.1123C>T (p.Arg375Cys)

CA8815176

290225 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 1b55986e-7cf8-4e67-b6e9-9a5b3073152c

Approved on: 2023-10-03

Published on: 2023-11-03

HGVS expressions

NM_000152.5:c.1123C>T
NM_000152.5(GAA):c.1123C>T (p.Arg375Cys)
NC_000017.11:g.80108536C>T
CM000679.2:g.80108536C>T
NC_000017.10:g.78082335C>T
CM000679.1:g.78082335C>T
NC_000017.9:g.75696930C>T
NG_009822.1:g.11981C>T
ENST00000302262.8:c.1123C>T
ENST00000302262.7:c.1123C>T
ENST00000390015.7:c.1123C>T
NM_000152.3:c.1123C>T
NM_001079803.1:c.1123C>T
NM_001079804.1:c.1123C>T
NM_000152.4:c.1123C>T
NM_001079803.2:c.1123C>T
NM_001079804.2:c.1123C>T
NM_001079803.3:c.1123C>T
NM_001079804.3:c.1123C>T

Uncertain Significance

• Met criteria codes: PM2_Supporting PM5_Supporting PP3

• Not Met criteria codes: PS3 PM3 PP4

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

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.1123 C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 375 (p.Arg375Cys). This variant has been detected in six individuals with abnormal newborn screening. Six patients with this variant had documented GAA deficiency with activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot. Of those individuals, 4 were compound heterozygous for the variant and a pathogenic variant (3 patients with c.-32-13T>G and with c.670C>T) and 3 of those were confirmed in trans by family testing (PMID: 36246652, internal laboratory). One individual was homozygous for the variant. However, all patients were detected through abnormal newborn screening and there is no evidence of symptoms or diagnosis of Pompe disease. Therefore PM3 and PP4 will not be applied. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001636 (5/30554 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). The computational predictor REVEL gives a score of 0.954 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another missense variant[ c.1124G>T p.Arg375Leu] (PMIDs: 24158270, 22081099) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting). Expression of the variant in HEK293 cells showed 11.7% GAA enzyme activity. However, this assay does not meet the requirements for use by the ClinGen Lysosomal Diseases VCEP because this percentage is above the cut off established by the assay (11%) to be considered deficient enzyme activity. There is a ClinVar entry for this variant (Variation ID: 290225, 1 star review status) with 2 submitters classifying the variant as likely pathogenic and 3 classifying the variant as a VUS. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (specifications Version 2.0): PM2_Supporting, PM5_Supporting, PP3. (Classification approved by the ClinGen Lysosomal Diseases VCEP on Oct. 3, 2023)

Met criteria codes

• PM2_Supporting: The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001636 (5/30554 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).
• PM5_Supporting: Another missense variant[ c.1124G>T p.Arg375Leu] (PMIDs: 24158270, 22081099) in the same codon has been classified as likely pathogenic for Pompe disease by the ClinGen Lysosomal Diseases VCEP (PM5_Supporting).
• PP3: The computational predictor REVEL gives a score of 0.954 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3).

Not Met criteria codes

• PS3: Expression of the variant in HEK293 cells showed 11.7% GAA enzyme activity. However, this assay does not meet the requirements for use by the ClinGen Lysosomal Diseases VCEP because this percentage is above the cut off established by the assay (11%) to be considered deficient enzyme activity.
• PM3: This variant has been detected in at least 6 individuals. Of those individuals, 4 were compound heterozygous for the variant and a pathogenic variant (3 patients with c.-32-13T>G and with c.670C>T) and 3 of those were confirmed in trans by family testing (PMID: 36246652, internal laboratory). One individual was homozygous for the variant. However, all patients were detected through abnormal newborn screening and there is no evidence of symptoms or diagnosis of Pompe disease. Therefore PM3 will not be applied.
• PP4: Six patients with this variant had documented GAA deficiency with activity in the affected range in muscle, cultured skin fibroblasts, leukocytes, lymphocytes, whole blood or dried blood spot (PMID: 36246652, internal laboratory). However, all patients were detected through abnormal newborn screening and there was no evidence of symptoms or diagnosis of Pompe disease. Therefore PP4 will not be applied.