ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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)

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).

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.

BP4

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.

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.