Submissions for variant NM_000152.5(GAA):c.2190-4G>A

gnomAD frequency: 0.00003  dbSNP: rs759974338

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001083210	SCV000626550	likely benign	Glycogen storage disease, type II	2023-12-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588046	SCV000695650	uncertain significance	not provided	2016-02-22	criteria provided, single submitter	clinical testing	Variant summary: c.2190-4G>A affects a non-conserved nucleotide, resulting in an intronic change. Mutation Taster predicts for a benign outcome. 5/5 programs via Alamut predict that this variant does not affect normal splicing. ESEfinder predicts changes of binding motifs for RNA splicing enhancers. This variant was found in 4/120722 control chromosomes at a frequency of 0.0000331, which does not exceed the maximal expected frequency of a pathogenic allele (0.0042205) in this gene. The variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant has been classified as a variant of uncertain significance (VUS) until additional information becomes available.
Eurofins Ntd Llc (ga)	RCV000588046	SCV000702692	uncertain significance	not provided	2016-11-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000588046	SCV000722619	likely benign	not provided	2021-03-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this variant does not alter splicing; Nucleotide substitution has no predicted effect on splicing and is not conserved across species
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001083210	SCV001422811	likely benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.2190-4G>A variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been reported as a VUS (by Integrated Genetics and EGL Genetic Diagnostics) and a likely benign variant (by GeneDx and Invitae) in ClinVar (Variation ID: 456393). This variant has been identified in 0.02982% (3/10062) of Ashkenazi Jewish chromosomes and 0.02603% (9/34578) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs759974338). 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 is located in the 3' plice region. 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. 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	RCV001083210	SCV001810181	uncertain significance	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003960261	SCV004768300	likely benign	GAA-related condition	2019-04-12	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001083210	SCV001455431	uncertain significance	Glycogen storage disease, type II	2020-01-24	no assertion criteria provided	clinical testing