Submissions for variant NM_000152.5(GAA):c.752C>T (p.Ser251Leu)

gnomAD frequency: 0.00038  dbSNP: rs200856561

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000372885	SCV000407270	likely pathogenic	Glycogen storage disease, type II	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000497864	SCV000590491	uncertain significance	not provided	2021-06-18	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: 25466677, 29122469, 27183828, 18458862, 24513544, 29451150, 29124014, 30555256, 31637888, 31980526)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000372885	SCV000626637	uncertain significance	Glycogen storage disease, type II	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 251 of the GAA protein (p.Ser251Leu). This variant is present in population databases (rs200856561, gnomAD 0.3%). The c.752C>T (p.Ser251Leu) variant frequently co-occurs with the c.761C>T (p.Ser254Leu) variant (rs577915581) in cis (on the same chromosome), which is known as the c.[752C>T;761C>T] haplotype. This haplotype has been reported in the literature as homozygous or in combination with other GAA variants in multiple individuals affected with Pompe disease (PMID: 24513544, 29124014, 27183828). The clinical significance of the c.752C>T variant alone is unclear and has not been reported in the literature in individuals with GAA-related disease. ClinVar contains an entry for this variant (Variation ID: 325781). 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. While the c.752C>T (p.Ser251Leu) variant alone has not been shown to affect GAA protein function, the c.[752C>T; 761C>T] haplotype has been reported to reduce enzyme activity (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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000372885	SCV001423076	likely pathogenic	Glycogen storage disease, type II	2020-01-29	criteria provided, single submitter	curation	The [p.Ser251Leu; p.Ser254Leu] complex variant in GAA has been reported in at least 15 individuals with Glycogen Storage Disease II (PMID: 24513544, 21232767, 27183828, 20080426), and has also been reported likely pathogenic by Illumina, pathogenic by GeneDx, and likely benign by Invitae in ClinVar (Variation ID: 325781, 325782). This variant has been identified in <0.28% of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200856561). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. In vitro functional studies provide some evidence that the p.Ser251Leu variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in the homozygous state and with a reported pathogenic variant, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Ser251Leu variant is pathogenic (PMID: 24513544, 21232767). The phenotype of homozygotes and heterozygotes with this variant is highly specific for Glycogen Storage Disease II based on GAA activity assays in relevant tissues and the absence of known pseudodeficiency alleles, consistent with disease (PMID: 24513544, 21232767). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PP4_moderate, PM3 (Richards 2015).
Baylor Genetics	RCV000372885	SCV001528211	uncertain significance	Glycogen storage disease, type II	2018-01-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000372885	SCV001810429	uncertain significance	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000497864	SCV002501221	likely pathogenic	not provided	2022-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265733	SCV002547855	uncertain significance	not specified	2024-08-19	criteria provided, single submitter	clinical testing	Variant summary: GAA c.752C>T (p.Ser251Leu) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 282488 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00035 vs 0.0042), allowing no conclusion about variant significance. c.752C>T has been reported in the literature as a complex allele in cis with c.761C>T (p.Ser254Leu) in settings of newborn screening for Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Labrousse_2010, Chien_2011, Liao_2014). This complex allele has been observed as a homozygous and compound heterozygous genotype in the ascertained reports. These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Glycogen Storage Disease, Type 2 (Pompe Disease). Co-occurrences of this complex allele in cis with other pathogenic variant(s) have been reported in the literature (GAA c.1411_1414del , p.E471PfsX5), providing supporting evidence for a benign role (example, Larousse_2010, Liao_2014, Yue_2024). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31228295, 21232767, 22644586, 20080426, 24513544, 38186848). ClinVar contains an entry for this variant (Variation ID: 325781). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000497864	SCV004224245	pathogenic	not provided	2022-11-22	criteria provided, single submitter	clinical testing	BP4
Fulgent Genetics, Fulgent Genetics	RCV000372885	SCV005653185	likely pathogenic	Glycogen storage disease, type II	2024-05-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000372885	SCV001132198	likely pathogenic	Glycogen storage disease, type II	2019-06-11	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751465	SCV005349331	uncertain significance	GAA-related disorder	2024-06-14	no assertion criteria provided	clinical testing	The GAA c.752C>T variant is predicted to result in the amino acid substitution p.Ser251Leu. This variant has been reported in individuals with glycogen storage disease 2, also called Pompe Disease (Tang et al. 2020. PubMed ID: 33073007; Fukuhara et al. 2017. PubMed ID: 29124014; Peng et al. 2016. PubMed ID: 27183828; Lee et al. 2019. PubMed ID: 31637888). This variant is reported in 0.28% of alleles in individuals of East Asian descent in gnomAD. The c.752C>T variant frequently occurs in cis with the c.761C>T (p.Ser254Leu) variant, and is known as the c.[752C>T;761C>T] haplotype. This haplotype has been reported in the homozygous or compound heterozygous state in multiple individuals with Pompe disease (Fukuhara et al. 2017. PubMed ID: 29124014; Peng et al. 2016. PubMed ID: 27183828). Of note, the c.[752C>T; 761C>T] (p.[Ser251Leu; Ser254Leu]) haplotype has been reported to be in cis with the c.1411_1414delGAGA variant (Labrousse et al. 2009. PubMed ID: 20080426; Chien et al. 2014. PubMed ID: 25466677; Mori et al. 2017. PubMed ID: 29122469). The c.[752C>T;761C>T] haplotype has been reported to significantly reduce GAA enzyme activity to 1.7-3.3% of wild-type activity (Kroos M et al 2012. PubMed ID: 22644586). ClinVar classifications for the c.752C>T variant range from uncertain, to likely pathogenic, to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/325781/), while one lab has classified the c.[752C>T;761C>T] haplotype as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/1321358/). Although we suspect that this variant may be pathogenic, at this time the clinical significance of this variant is uncertain.