Submissions for variant NM_000152.5(GAA):c.658G>T (p.Val220Leu)

gnomAD frequency: 0.00007  dbSNP: rs530478036

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000631081	SCV001443284	likely benign	Glycogen storage disease, type II	2023-04-04	reviewed by expert panel	curation	The NM_000152.5:c.658G>T variant is GAA is a missense variant that is predicted to result in the substitution of valine by leucine at amino acid 220 (p.Val220Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00075 (15/19928 alleles) in the East Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS-7 cells, this variant results in normal GAA activity, and the protein is normally synthesized and/or processed (PMID 22644586) (BS3_Supporting). The computational predictor REVEL gives a score of 0.305 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). The variant has been reported in an individual with either suspected Pompe disease or a known carrier, but further details are not available (PMID 22644586). There is a ClinVar entry for this variant (Variation ID: 255365). While there is conflicting evidence, overall, the benign evidence, including functional studies (BS3_Supporting) and in silico data (BP4), outweighs the pathogenic evidence (PM2_Supporting). Therefore, the variant has been classified as likely benign. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PM2_Supporting, BP4, BS3_Supporting (modified classification: likely benign, approved by ClinGen Lysosomal Diseases Variant Curation Expert Panel, April 4, 2023).
PreventionGenetics, part of Exact Sciences	RCV000244709	SCV000302694	likely benign	not specified		criteria provided, single submitter	clinical testing
Invitae	RCV000631081	SCV000752074	uncertain significance	Glycogen storage disease, type II	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 220 of the GAA protein (p.Val220Leu). This variant is present in population databases (rs530478036, gnomAD 0.07%). This missense change has been observed in individual(s) with GAA-related disease (PMID: 22644586). ClinVar contains an entry for this variant (Variation ID: 255365). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GAA protein function. Experimental studies have shown that this missense change does not substantially affect GAA function (PMID: 22644586). 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.
Ambry Genetics	RCV002374412	SCV002667166	uncertain significance	Cardiovascular phenotype	2021-02-10	criteria provided, single submitter	clinical testing	The p.V220L variant (also known as c.658G>T), located in coding exon 2 of the GAA gene, results from a G to T substitution at nucleotide position 658. The valine at codon 220 is replaced by leucine, an amino acid with highly similar properties. This variant was reported in a cohort of known or suspected Pompe disease cases; however, studies suggested no significant functional impact (Kroos M et al. Hum Mutat, 2012 Aug;33:1161-5). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000631081	SCV002786049	uncertain significance	Glycogen storage disease, type II	2021-09-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000631081	SCV001453593	uncertain significance	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing