Submissions for variant NM_000152.5(GAA):c.2332-12A>T

gnomAD frequency: 0.00178  dbSNP: rs200965268

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723547	SCV000110008	uncertain significance	not provided	2012-09-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000244544	SCV000302677	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000723547	SCV000530270	likely benign	not provided	2020-12-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000244544	SCV001361266	likely benign	not specified	2019-04-11	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2332-12A>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00055 in 274190 control chromosomes, predominantly at a frequency of 0.0058 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 1.37 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) phenotype (0.0042), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.2332-12A>T in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248964	SCV001422770	likely benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.2332-12A>T variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS by EGL Genetic Diagnostics and a likely benign variant by GeneDx and PreventionGenetics in ClinVar (Variation ID: 92475). This variant has been identified in 0.573% (142/24770) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200965268). This variant has been seen in the general population at a greater frequency than expected for Glycogen Storage Disease II and is consistent with a benign role. Computational 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: BS1, BP4, BP7 (Richards 2015).
Invitae	RCV001248964	SCV001731834	benign	Glycogen storage disease, type II	2024-01-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001248964	SCV002048529	likely benign	Glycogen storage disease, type II	2023-09-22	criteria provided, single submitter	clinical testing