Submissions for variant NM_000152.5(GAA):c.1828G>A (p.Ala610Thr)

gnomAD frequency: 0.00004  dbSNP: rs144731405

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000689295	SCV002817446	uncertain significance	Glycogen storage disease, type II	2022-10-18	reviewed by expert panel	curation	The NM_000152.5:GAA:c.1828G>A variant in GAA is a missense variant predicted to cause substitution of Ala by Thr at amino acid 610 (p.Ala610Thr). Two patients with this variant have been reported in the literature (PMID: 32504392, 35775064). However, because the diagnosis of Pompe disease was unclear for both patients, neither PP4 nor PM3 was applied. One of these patients, a 4-year-old girl with IOPD identified as homozygous for GAA:c.1828G>A, was also diagnosed with congenital myasthenia syndrome type 5. Because her symptoms, which included bradycardia, poor suckling, respiratory distress, respiratory failure, subglottic stenosis, and tachypnea, could be related to congenital myasthenia syndrome and not Pompe disease, and GAA activity was unavailable, this data was not used as evidence to support pathogenicity of the variant. Another individual was reported to be compound heterozygous for c.1828G>A and c.1966-1968del, but clinical information regarding the presence or absence of clinical symptoms of Pompe disease, and GAA activity was unavailable. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00017 (1/5976 alleles) in the Other population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.641 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function (neither PP3 nor BP4 is met), and the computational splicing predictor SpliceAI gives a score of 0.00 for donor/acceptor loss suggesting that the variant has no impact on splicing. Another missense variant c.1829C>T (p.Ala610Val) in the same codon has been reported (PMID: 21484825, 17643989). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP (PM5 not met). There is a ClinVar entry for this variant (Variation ID: 282242, 2 star review status) with 5 submitters classifying the variant as Uncertain significance and 1 submitter classifying it as Pathogenic. In summary, this variant meets the criteria to be classified as 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): PM2_Supporting. (Classification approved by the ClinGen LSD VCEP on Oct. 18, 2022).
Eurofins Ntd Llc (ga)	RCV000269526	SCV000333598	uncertain significance	not provided	2018-07-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689295	SCV000816938	uncertain significance	Glycogen storage disease, type II	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 610 of the GAA protein (p.Ala610Thr). This variant is present in population databases (rs144731405, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 282242). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000689295	SCV001287876	uncertain significance	Glycogen storage disease, type II	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV000689295	SCV001786768	uncertain significance	Glycogen storage disease, type II	2021-07-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000689295	SCV002793740	uncertain significance	Glycogen storage disease, type II	2021-08-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000689295	SCV004807655	uncertain significance	Glycogen storage disease, type II	2024-03-29	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000689295	SCV001459737	uncertain significance	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000689295	SCV001469242	pathogenic	Glycogen storage disease, type II	2020-10-11	no assertion criteria provided	clinical testing