Submissions for variant NM_000152.5(GAA):c.1048G>A (p.Val350Met)

gnomAD frequency: 0.00007  dbSNP: rs200412003

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000671932	SCV000814652	pathogenic	Glycogen storage disease, type II	2024-01-31	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 350 of the GAA protein (p.Val350Met). This variant is present in population databases (rs200412003, gnomAD 0.05%). This missense change has been observed in individual(s) with Pompe disease (PMID: 23430949, 25451853, 36246652). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 555998). 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 expected to disrupt GAA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GAA function (PMID: 36246652). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000671932	SCV001422742	uncertain significance	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Val350Met variant in GAA has been reported in 2 individuals with glycogen storage disease II (PMID: 25786784, 25451853) and has been identified in 0.04% (11/25122) of European (Finnish) chromosomes, 0.013% (17/128822) of European (non-Finnish) chromosomes, and 0.004% (1/24900) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200412003). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar as a VUS by Counsyl and Invitae (VariationID: 555998). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals heterozygous for this variant is highly specific for glycogen storage disease II based on GAA enzyme activity in muscle and lymphocytes being <10% of wild type, consistent with disease (PMID: 25786784, 25451853). Additionally, the presence of this variant in combination with reported pathogenic variant c.-32-13T>G and in individuals with glycogen storage disease II slightly increases the likelihood that the p.Val350Met variant is pathogenic. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_supporting, PM2, PP3, PP4 (Richards 2015).
GeneDx	RCV001576168	SCV001803300	uncertain significance	not provided	2020-11-04	criteria provided, single submitter	clinical testing	Reported previously as heterozygous along with another variant in the GAA gene in an asymptomatic adult with decreased alpha glucosidase activity in multiple tissues (Echaniz-Laguna et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23430949, 25786784, 24627108, 25451853)
Genome-Nilou Lab	RCV000671932	SCV002027250	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000671932	SCV002060332	uncertain significance	Glycogen storage disease, type II	2021-11-08	criteria provided, single submitter	clinical testing	NM_000152.3(GAA):c.1048G>A(V350M) is a missense variant classified as a variant of uncertain significance in the context of Pompe disease. V350M has been observed in cases with relevant disease (PMID 25451853, 23430949). Functional assessments of this variant are not available in the literature. V350M has been observed in population frequency databases (gnomAD: FIN 0.05%). In summary, there is insufficient evidence to classify NM_000152.3(GAA):c.1048G>A(V350M) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307586	SCV002600693	uncertain significance	not specified	2022-10-24	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1048G>A (p.Val350Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 251022 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (9.6e-05 vs 0.0042), allowing no conclusion about variant significance. c.1048G>A has been reported in the literature as heterozygous occurrence, along with a known pathogenic variant, in individual(s) with asymptomatic Pompe disease/Pompe disease presenting with a pure vascular phenotype, and with decreased alpha glucosidase activity in different tissues (Echaniz-Laguna_2015, Quenardelle_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000671932	SCV002777400	uncertain significance	Glycogen storage disease, type II	2021-09-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001576168	SCV003816227	uncertain significance	not provided	2023-11-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001576168	SCV004010576	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	GAA: PM2, PM3, PS3:Supporting
Baylor Genetics	RCV000671932	SCV004195428	likely pathogenic	Glycogen storage disease, type II	2023-10-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000671932	SCV001455600	uncertain significance	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing