Submissions for variant NM_000152.5(GAA):c.2395C>T (p.His799Tyr)

gnomAD frequency: 0.00019  dbSNP: rs143347747

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000692315	SCV004042613	uncertain significance	Glycogen storage disease, type II	2023-09-05	reviewed by expert panel	curation	The NM_000152.5:c.2395C>T variant in GAA is a missense variant predicted to cause substitution of His by Tyr at amino acid 799 (p.His799Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00038 (6/15954 alleles) in the African population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.443 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). It only has been reported in one case as LOPD, in which has unknown phase concurrence in compound heterozygous with c.-32-13T>G (PMID: 22958975). Thus met PM3_supporting. The LOPD case has been reported to have GAA residue level 0.25 (normal cutoff unknown. But average of 20 LOPD patients is 8.35, so <10% of normal mean control level). Thus PP4_moderate is applied. There is a ClinVar entry for this variant (Variation ID: 284886, 2 star review status) with 8 submitters classifying the variant as Uncertain significance with no conflicts. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP4_moderate, PM3_supporting, BP4. (Classification approved by the ClinGen Lysosomal Diseases VCEP, September 5, 2023)
Eurofins Ntd Llc (ga)	RCV000297755	SCV000337689	uncertain significance	not provided	2015-12-31	criteria provided, single submitter	clinical testing
Invitae	RCV000692315	SCV000820130	uncertain significance	Glycogen storage disease, type II	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 799 of the GAA protein (p.His799Tyr). This variant is present in population databases (rs143347747, gnomAD 0.03%). This missense change has been observed in individual(s) with Pompe disease (PMID: 22958975). ClinVar contains an entry for this variant (Variation ID: 284886). 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. 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.
Mendelics	RCV000692315	SCV001140843	uncertain significance	Glycogen storage disease, type II	2023-05-07	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000692315	SCV001422808	uncertain significance	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.His799Tyr variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been identified in 0.038% (6/15954) of African chromosomes, 0.006% (2/34532) of Latino chromosomes, and 0.005% (1/18354) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs143347747). 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 as a VUS by EGL Genetic Diagnostics and Invitae in ClinVar (Variation ID: 284886). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The Histidine (His) at position 799 is not highly conserved in mammals and evolutionary distant species, and 5 species (nile tilapia, princess of Burundi, burton's mouthbreather, zebra mbuna, pundamilia nyererei) carry a Tyrosine (Tyr), raising the possibility that this change at this position may be tolerated. In summary, the clinical significance of the p.His799Tyr variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4 (Richards 2015).
Genome-Nilou Lab	RCV000692315	SCV001810191	uncertain significance	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002229745	SCV002511403	uncertain significance	not specified	2022-04-01	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2395C>T (p.His799Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 150978 control chromosomes, predominantly within the Latino and African subpopulations at a frequency of 0.00092 and 0.00031, respectively, in the gnomAD database (v3.1 genomes dataset). These frequencies are not significantly higher than the estimated maximum expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.0042), allowing no conclusion about variant significance. The variant, c.2395C>T, has been reported in the literature in a compound heterozygote individual affected with the late form of Glycogen Storage Disease Type 2 (Pompe Disease) (Musumeci_2012), however, in a later report this patient was noted to carry two co-occurring (potentially) pathogenic variants, which could explain the phenotype, although the phase of the three variants was not specified (Montagnese_2015). These reports 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000297755	SCV003828482	uncertain significance	not provided	2020-06-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000692315	SCV001463860	uncertain significance	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing