Submissions for variant NM_000152.5(GAA):c.525_526del (p.Asn177fs)

dbSNP: rs767882689

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000169454	SCV001443304	pathogenic	Glycogen storage disease, type II	2020-11-02	reviewed by expert panel	curation	This variant, c.525_526del (p.Asn177ProfsTer11), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by the finding of this variant in an individual with no GAA cross-reactive immunological material in cultured skin fibroblasts (PMID 22252923, 23825616, 31342611). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003288 in the South Asian population, meeting PM2. One individual with Pompe disease and meeting the ClinGen LSD VCEP's specifications for PP4 has been reported in the literature (PMID 22252923, 23825616). This patient is homozygous for the variant, meeting PM3_Supporting. Two other individuals with the variant have been reported. One is homozygous (PMID 25455803; different than the individual reported in PMID 25455803 based on the age at diagnosis) another individual who is compound heterozygous for the variant and c.-32-13T>G (PMID 31392188). However, these patients were not included because the residual activity was not provided, and therefore PP4 cannot be assessed, and PM3 was not applied. There is a ClinVar entry for this variant (Variation ID: 189057, 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specific by the ClinGen LSD VCEP: PVS1, PM2, PM3_Supporting, PP4.
Counsyl	RCV000169454	SCV000220875	likely pathogenic	Glycogen storage disease, type II	2014-11-11	criteria provided, single submitter	literature only
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169454	SCV001422878	likely pathogenic	Glycogen storage disease, type II	2020-01-23	criteria provided, single submitter	curation	The p.Asn177ProfsTer11 variant in GAA has been reported in 6 individuals (including 2 Middle Eastern and 1 Asian individual) with Glycogen Storage Disease II (PMID: 22252923, 23825616, 25455803; DOI: 10.1016/j.ymgme.2017.12.198), and has also been reported in ClinVar (Variation ID: 189057). This variant has been identified in 0.0033% (1/30410) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs767882689). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 177 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. This variant is noted as homozygous in two individuals with Glycogen Storage Disease II (PMID: 23825616, 25455803). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169454	SCV004297577	pathogenic	Glycogen storage disease, type II	2023-02-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189057). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 22252923). This variant is present in population databases (rs767882689, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Asn177Profs*11) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923).