Variant: NM_000152.5(GAA):c.2132_2133delinsGG (p.Thr711Arg)

CA658658713

456391 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: d6218fc3-a53b-48db-a17a-143dc496de6a

Approved on: 2022-09-19

Published on: 2022-09-19

HGVS expressions

NM_000152.5:c.2132_2133delinsGG
NM_000152.5(GAA):c.2132_2133delinsGG (p.Thr711Arg)
NC_000017.11:g.80113309_80113310delinsGG
CM000679.2:g.80113309_80113310delinsGG
NC_000017.10:g.78087108_78087109delinsGG
CM000679.1:g.78087108_78087109delinsGG
NC_000017.9:g.75701703_75701704delinsGG
NG_009822.1:g.16754_16755delinsGG
ENST00000302262.8:c.2132_2133delinsGG
ENST00000302262.7:c.2132_2133delinsGG
ENST00000390015.7:c.2132_2133delinsGG
ENST00000572080.1:n.551_552delinsGG
NM_000152.3:c.2132_2133delinsGG
NM_001079803.1:c.2132_2133delinsGG
NM_001079804.1:c.2132_2133delinsGG
NM_000152.4:c.2132_2133delinsGG
NM_001079803.2:c.2132_2133delinsGG
NM_001079804.2:c.2132_2133delinsGG
NM_001079803.3:c.2132_2133delinsGG
NM_001079804.3:c.2132_2133delinsGG

Uncertain Significance

• Met criteria codes: PP3

• Not Met criteria codes: PS1 PM2

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.2132_2133delinsGG variant in GAA is a multinucleotide variant predicted to cause substitution of threonine by arginine at amino acid 711 (p.Thr711Arg). The same amino acid change, resulting from one of the two nucleotide changes observed in this multinucleotide variant, c.2132C>G, has been reported in a patient with Pompe disease (PMID: 20080426, 31342611). However, this other variant has conflicting evidence for pathogenicity based on guidelines by the ClinGen LSD VCEP (PMID: 18425781). The minor allele frequency of the c.2132C>G variant in gnomAD v2.1.1 is 0.001258 (23/18290 alleles) in the East Asian population, but was only seen in phase with c.2133A>G in 23 of the 24 heterozygotes reported in gnomAD v2.1.1. Therefore, the highest possible population minor allele frequency in gnomAD v2.1.1 is 0.001258 (23/18290 alleles) in the East Asian population (none of the population data codes are met). The computational predictors PROVEAN, Mutation Taster, and MutPredIndel suggest that this variant has a deleterious effect on the GAA gene, evidence that correlates with impact to GAA function (PP3). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 456391, 1 star review status) with 2 submitters, 1 submitter classifying the variant as likely pathogenic and 1 submitter classifying the variant as a variant of uncertain significance. 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 Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3.

Met criteria codes

• PP3: The computational predictors PROVEAN, Mutation Taster, and MutPredIndel suggest that this variant has a deleterious effect on the GAA gene, evidence that correlates with impact to GAA function.

Not Met criteria codes

• PS1: The same amino acid change, resulting from a different nucleotide change c.2132C>G, has been reported in a patient with Pompe disease (PMID: 20080426, 31342611). However, this other variant has conflicting evidence for pathogenicity based on guidelines by the ClinGen LSD VCEP (PMID: 18425781).
• PM2: While gnomAD does not list an allele frequency for c.2132_2133delinsGG, c.2132C>G is noted to be a multinucleotide variant, occurring with c.2133A>G in 23 individuals; i.e. all of these individuals have c. c.2132_2133delinsGG. While the ethnicity of these idividuals is not known, 23 allele with c.2132C>G occir in East Asian and 1 allele is the “other” population. Therefore, the frequency of c.2132_2133delinsGG would be approximately 23/18290 (E Asian)+6574 (other) = 23/24864 = 0.000925. However, under the assumption that all individuals with the two variants in cis are East Asian, the frequency would be 0.00126, which does not meet the allele frequency cut-off for PM2_Supporting (<0.001).