Submissions for variant NM_000152.5(GAA):c.688G>A (p.Val230Met)

dbSNP: rs145866792

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000542661	SCV001371696	uncertain significance	Glycogen storage disease, type II	2023-03-13	reviewed by expert panel	curation	The NM_000152.5:c.688G>A variant in GAA is a missense variant predicted to result in the substitution of valine by methionine at amino acid 230 (p.Val230Met). The highest population minor allele frequency in gnomAD v2.1.1. is 0.002261 (56/24772 alleles) in the African/African American population. This allele frequency meets neither the PM2 allele frequency threshold (<0.001) nor the BS1 allele frequency threshold (>0.005) specified by the ClinGen Lysosomal Diseases VCEP. The computational predictor REVEL gives a score of 0.482 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). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of experimental studies are not available. There is a ClinVar entry for this variant (Variation ID: 196222). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease due to insufficient evidence. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BP4. (Classification approved by the ClinGen Lysosomal Diseases VCEP, March 13, 2023).
Eurofins Ntd Llc (ga)	RCV000724048	SCV000228795	uncertain significance	not provided	2018-08-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000194005	SCV000247442	uncertain significance	not specified	2015-03-09	criteria provided, single submitter	clinical testing
Invitae	RCV000542661	SCV000626626	likely benign	Glycogen storage disease, type II	2024-01-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000542661	SCV000895137	uncertain significance	Glycogen storage disease, type II	2021-08-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000724048	SCV001791057	uncertain significance	not provided	2021-05-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 7603530, 9425285)
Ambry Genetics	RCV002362904	SCV002667036	uncertain significance	Cardiovascular phenotype	2015-12-22	criteria provided, single submitter	clinical testing	The p.V230M variant (also known as c.688G>A), located in coding exon 2 of the GAA gene, results from a G to A substitution at nucleotide position 688. The valine at codon 230 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly 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.
Revvity Omics, Revvity	RCV000724048	SCV003816224	uncertain significance	not provided	2019-12-08	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000724048	SCV000925086	uncertain significance	not provided	2018-02-06	no assertion criteria provided	provider interpretation	Found in a 23-year-old female with unexplained postpartum sudden cardiac arrest, along with 5 other VUSs. p.Val230Met (c.688G>A) in exon 3 of the GAA gene (NM_000152.3) Chromosome location 17-78079689-G-A Based on the information reviewed below, we classify this as a Variant of Uncertain Significance (VUS). This variant has not been reported in the literature in association with disease, according to the Invitae report. Of note: The GAA gene is associated with autosomal recessive glycogen storage disease type II (GSDII), also known as Pompe disease (MedGen UID: 5340). Our adult patient does not display any known clinical symptoms of Pompe, and because this is a recessive condition she would need to have a disease-causing variant in each allele in order to have the condition. This one variant in one allele would not be sufficient, even if it were pathogenic. This is a conservative amino acid change, resulting in the replacement of a nonpolar Valine with a nonpolar Methionine. Valine at this location is highly conserved across ~100 vertebrate species for which we have data. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant was reported in 74 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall MAF: 0.03%. It is most prevalent among individuals with either African or Latino ancestry (like our patient). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.
Natera, Inc.	RCV000542661	SCV001453414	uncertain significance	Glycogen storage disease, type II	2020-01-17	no assertion criteria provided	clinical testing