Submissions for variant NM_000152.5(GAA):c.1408_1410del (p.Asn470del)

dbSNP: rs748893499

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001200863	SCV001371732	pathogenic	Glycogen storage disease, type II	2020-05-05	reviewed by expert panel	curation	This variant, c.1408_1410del (p.Asn470del), results in an in frame deletion of a single amino acid in GAA, meeting PM4_Supporting. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005447 in the East Asian population, meeting PM2. This variant was found in two Spanish individuals with infantile-onset Pompe disease, who meet the ClinGen LSD VCEP's PP4 specifications, in compound heterozygosity with c.1222A>G (p.Met408Val) (PMIDs 11738358, 17616415). In one patient, the phase was confirmed in trans (PMID 11738358). This in trans data meets PM3. When expressed in COS-7 cells, this variant had 1.4% wild type GAA activity, meeting PS3 (PMID 19862843). PROVEAN and Mutation Taster predict that this variant is deleterious, meeting PP3. There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as a pathogenic variant for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3, PM4_Supporting, PP3, PP4.
Revvity Omics, Revvity	RCV001780107	SCV002025220	likely pathogenic	not provided	2020-04-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001200863	SCV002108969	likely pathogenic	Glycogen storage disease, type II	2023-03-17	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects GAA function (PMID: 19862843). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 932895). This variant has been observed in individual(s) with Pompe disease (PMID: 11738358, 31086307, 34530085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs748893499, gnomAD 0.006%). This variant, c.1408_1410del, results in the deletion of 1 amino acid(s) of the GAA protein (p.Asn470del), but otherwise preserves the integrity of the reading frame.
Fulgent Genetics, Fulgent Genetics	RCV001200863	SCV002797699	pathogenic	Glycogen storage disease, type II	2022-03-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001200863	SCV004195480	pathogenic	Glycogen storage disease, type II	2023-09-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751912	SCV005366302	likely pathogenic	GAA-related disorder	2024-08-08	no assertion criteria provided	clinical testing	The GAA c.1408_1410delAAC variant is predicted to result in an in-frame deletion (p.Asn470del). This variant has been reported in the compound heterozygous state in an individual with glycogen storage disease 2, also known as Pompe disease (Patient 2, Fernandez-Hojas et al. 2002. PubMed ID: 11738358). This variant has also been reported in a comprehensive cohort of US children and adolescents with Pompe disease (Supplementary Table S3, Kishnani et al. 2019. PubMed ID: 31086307) and in a study of Spanish patients with Pompe disease (Amiñoso et al. 2021. PubMed ID: 34530085). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic.