Submissions for variant NM_000152.5(GAA):c.1933G>C (p.Asp645His)

dbSNP: rs368438393

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169400	SCV000220797	likely pathogenic	Glycogen storage disease, type II	2014-10-14	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169400	SCV001228299	pathogenic	Glycogen storage disease, type II	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 645 of the GAA protein (p.Asp645His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with infantile Pompe disease (PMID: 7695647, 12897283). ClinVar contains an entry for this variant (Variation ID: 189013). 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: 7695647). This variant disrupts the p.Asp645 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9535769, 15145338, 21039225, 21439876, 24269976). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169400	SCV001422907	pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Asp645His variant in GAA has been reported in two individuals from Taiwan with Glycogen Storage Disease II (PMID: 12897283, 7695647), and has also been reported likely pathogenic by Counsyl in ClinVar (Variation ID: 189013). This variant has been identified in 0.006% (1/18070) of East Asian chromosomes and 0.005% (1/20588) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs368438393). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies with COS cells transfected with this variant provide some evidence that the p.Asp645His variant may impact GAA activity, but not GAA levels (PMID: 19862843, 7695647). However, these types of assays may not accurately represent biological function. 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 presence of this variant in the homozygous state in two individuals with Glycogen Storage Disease II increases the likelihood that the p.Asp645His variant is pathogenic (PMID: 12897283, 7695647). Three additional variants at the the same position (p.Asp645Tyr, p.Asp645Asn, p.Asp645Glu), including 2 pathogenic variants curated by our study, have been reported in association with disease in ClinVar, suggesting that a change at this position may not be tolerated (Variation ID: 556386, 188728, 4029). The phenotype of two individuals homozygous for this variant is highly specific for Glycogen Storage Disease II based on abnormally low GAA activity detected by assays with fibroblast cells (PMID: 7695647, 12897283). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies and multiple occurrences of pathogenic missense variants at the same position. ACMG/AMP Criteria applied: PM5_Strong, PS3, PM2, PM3, PP3, PP4 (Richards 2015).
Baylor Genetics	RCV000169400	SCV004197850	pathogenic	Glycogen storage disease, type II	2024-03-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003488416	SCV004236284	pathogenic	not provided	2023-10-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169400	SCV005185673	pathogenic	Glycogen storage disease, type II	2024-05-16	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1933G>C (p.Asp645His) results in a non-conservative amino acid change located in the Glycoside hydrolase family 31, TIM barrel domain (IPR000322) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 242414 control chromosomes. c.1933G>C has been reported in the literature in homozygous and compound heterozygous individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Kishnani_2019, Lin_1995, Ngiwsara_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal acid alpha-glucosidase activity in COS-1 (Lin_1995). The following publications have been ascertained in the context of this evaluation (PMID: 31086307, 7695647, 31510962). ClinVar contains an entry for this variant (Variation ID: 189013). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV000169400	SCV001459741	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing