Submissions for variant NM_000152.5(GAA):c.1630G>A (p.Val544Met)

gnomAD frequency: 0.00009  dbSNP: rs567695610

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000804034	SCV005089706	uncertain significance	Glycogen storage disease, type II	2024-06-06	reviewed by expert panel	curation	The NM_000152.5:c.1630G>A variant in GAA is a missense variant predicted to cause substitution of valine by methionine at amino acid 544 (p.Val544Met). This variant has not been reported in the literature in patients with Pompe disease. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00028 (7/ 24886 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion. The computational predictor REVEL gives a score of 0.340 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). There is a ClinVar entry for this variant (Variation ID: 664232; 2 star review status) with two submitters 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 Diseases Variant Curation Expert panel (Specifications Version 2.0): PM3_supporting, BP4. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on June 6, 2024)
GeneDx	RCV000734310	SCV000618932	uncertain significance	not provided	2024-05-06	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22253258, 19343043)
Eurofins Ntd Llc (ga)	RCV000734310	SCV000862441	uncertain significance	not provided	2018-07-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804034	SCV000943925	uncertain significance	Glycogen storage disease, type II	2025-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 544 of the GAA protein (p.Val544Met). This variant is present in population databases (rs567695610, gnomAD 0.03%). 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: 450358). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GAA protein function with a negative predictive value of 95%. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000804034	SCV001160481	uncertain significance	Glycogen storage disease, type II	2019-05-05	criteria provided, single submitter	clinical testing	The GAA c.1629_1630delinsTA; p.Val544Met variant, to our knowledge, is not reported in the medical literature or gene-specific databases. This variant deletes two nucleotides and inserts two nucleotides, resulting in an in-frame amino acid substitution. Two individual single nucleotide variants (c.1629C>T and c.1630G>A) that together comprise the c.1629_1630delinsTA variant are each reported in ClinVar (Variation ID: 510672 and 450358). The c.1629_1630delinsTA variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), although c.1629C>T (24/250706 alleles) and c.1630G>A (18/282078 alleles) are both reported at low frequency in the general population. The valine at codon 544 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, other amino acid substitutions at adjacent residues (p.Tyr543Asp and p.Pro545Leu) are reported in individuals with glycogen storage disease type II and are considered disease-causing (Flanagan 2009, Sifi 2017), suggesting this region of the protein is functionally important. Still, given the lack of clinical and functional data, the significance of the p.Val544Met variant is uncertain at this time. References: Flanagan JJ et al. The pharmacological chaperone 1-deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha-glucosidase. Hum Mutat. 2009 Dec;30(12):1683-92. Sifi Y et al. Clinical Analysis of Algerian Patients with Pompe Disease. J Neurodegener Dis. 2017;2017:9427269.
Mayo Clinic Laboratories, Mayo Clinic	RCV000734310	SCV001713740	uncertain significance	not provided	2020-12-21	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000804034	SCV002027279	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000804034	SCV002791180	uncertain significance	Glycogen storage disease, type II	2021-10-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000734310	SCV003834078	uncertain significance	not provided	2023-09-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000804034	SCV002092050	uncertain significance	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing