Submissions for variant NM_000152.5(GAA):c.510C>T (p.Asp170=)

gnomAD frequency: 0.00005  dbSNP: rs564758226

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001084686	SCV004809076	uncertain significance	Glycogen storage disease, type II	2024-03-19	reviewed by expert panel	curation	The NM_000152.5:c.510C>T variant in GAA is a synonymous (silent) variant (p.Asp170=) that is not predicted to impact splicing (BP7, BP4). This variant has been detected in at least 14 individuals with Pompe disease (PMIDs 14695532, 30564623, 30922962, 34405923). However, in all but one individual it was found to co-occur with two additional GAA variants. Additionally, studies have shown that c.510C>T frequently occurs in cis with the c.-32-13T>G variant (pathogenic by the ClinGen Lysosomal Disease VCEP) and is associated with an earlier age of onset and lower GAA enzyme activity in fibroblasts compared to individuals with c.-32-13T>G that do not carry c.510C>T (PMIDs 30922962, 34405923). RT-PCR from patients with c.510C>T and c.-32-13T>G and minigene assays demonstrate that c.510C>T modulates the aberrant splicing caused by c.-32-13T>G, but does not have a significant impact on splicing when it occurs in isolation (PMID 30922962). The highest population minor allele frequency in gnomAD v2.1.1. is 0.00008925 (11/123248 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 280956). While it is uncertain if c.510C>T is causative of disease, there is evidence suggesting that this variant acts as a negative modifying factor when it occurs in cis with c.-32-13T>G. Therefore, this variant is classified as a variant of unknown 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): BP4, BP7, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on March 19, 2024).
Eurofins Ntd Llc (ga)	RCV000293574	SCV000330941	uncertain significance	not provided	2015-09-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084686	SCV000626616	likely benign	Glycogen storage disease, type II	2025-01-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001084686	SCV001281247	uncertain significance	Glycogen storage disease, type II	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001084686	SCV001422662	likely benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.510C>T (p.Asp170=) variant in GAA has been reported as a polymorphism in 1 Dutch individual with Glycogen Storage Disease II (PMID: 14695532), and has also been identified in 0.009% (11/123248) of European (non-Finnish) chromosomes chromosomes and 0.006% (2/35320) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs564758226). 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 been reported as a VUS by EGL Genetic Diagnostics and a likely benign variant by Invitae in ClinVar (Variation ID: 280956). Computational splicing prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. However, novel synonymous variants supported by computational evidence without raised suspicion for an impact are likely benign (Richards 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: PM2, BP7, BP4 (Richards 2015).
Genome-Nilou Lab	RCV001084686	SCV001810262	uncertain significance	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000293574	SCV003816226	uncertain significance	not provided	2023-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165718	SCV003911880	likely benign	Cardiovascular phenotype	2024-09-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323485	SCV004030047	likely benign	not specified	2023-07-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000293574	SCV005050846	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	GAA: BP4, BP7