Submissions for variant NM_000152.5(GAA):c.32G>A (p.Arg11Gln)

gnomAD frequency: 0.00026  dbSNP: rs138812846

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000250396	SCV000302687	likely benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000724696	SCV000331867	uncertain significance	not provided	2015-10-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525907	SCV000626605	likely benign	Glycogen storage disease, type II	2025-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000724696	SCV000716344	likely benign	not provided	2020-09-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18425781, 31301153)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000250396	SCV000919371	uncertain significance	not specified	2018-05-25	criteria provided, single submitter	clinical testing	Variant summary: GAA c.32G>A (p.Arg11Gln) 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 0.00014 in 275638 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00014 vs 0.0042), allowing no conclusion about variant significance. The variant, c.32G>A, has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Kroos_2008) but was classified as not pathogenic by the authors. These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Kroos_2008). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign x1, uncertain significance 2x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000525907	SCV001810613	uncertain significance	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000724696	SCV003828513	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004992133	SCV005591976	uncertain significance	Cardiovascular phenotype	2024-09-19	criteria provided, single submitter	clinical testing	The p.R11Q variant (also known as c.32G>A), located in coding exon 1 of the GAA gene, results from a G to A substitution at nucleotide position 32. The arginine at codon 11 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported as co-occurring with other GAA variants in an individual with Pompe disease; however, additional details were limited (Kroos M et al. Hum Mutat, 2008 Jun;29:E13-26). Functional studies by one group suggested that this variant may not significantly impact enzyme function, and a minigene study suggested that this variant may impact splicing; however, additional evidence is needed to confirm these findings (Kroos M et al. Hum Mutat, 2008 Jun;29:E13-26; Goina E et al. Hum Mutat, 2019 Nov;40:2121-2130). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.