Submissions for variant NM_000152.5(GAA):c.1286A>G (p.Gln429Arg)

gnomAD frequency: 0.00026  dbSNP: rs200294882

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000528796	SCV001371699	benign	Glycogen storage disease, type II	2020-01-22	reviewed by expert panel	curation	The highest continental population minor allele frequency for c.1286A>G (p.Gln429Arg) in gnomAD v2.1.1 is 0.01028 in the East Asian population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 284497; 2 star review status) with three submitters classifying the variant as benign and one as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1.
Eurofins Ntd Llc (ga)	RCV000346911	SCV000337146	benign	not specified	2015-11-12	criteria provided, single submitter	clinical testing
GeneDx	RCV001533532	SCV000519877	benign	not provided	2020-10-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27183828, 25466677)
Invitae	RCV000528796	SCV000626502	benign	Glycogen storage disease, type II	2024-01-31	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852731	SCV000995446	benign	Cardiomyopathy	2017-03-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000528796	SCV001281356	uncertain significance	Glycogen storage disease, type II	2017-05-05	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000346911	SCV001361535	benign	not specified	2019-08-09	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1286A>G (p.Gln429Arg) 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 0.0008 in 234302 control chromosomes, predominantly at a frequency of 0.011 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.6 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). In addition, the variant was also found in Japanese healthy controls with a frequency of 0.005, including 1 homozygote (in the HGVD database). These data strongly suggest that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.1286A>G, has been reported in the literature in a newborn affected with infantile-onset Glycogen Storage Disease, Type 2 (Pompe Disease), however, this patient also carried two other pathogenic GAA variants, in cis (c.1062 C>G (p.Tyr354X)), and trans (c.1935C>A (p.Asp645Glu)) that could explain the phenotype, therefore supporting a benign role for the variant of interest (Chien_2014, Peng_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as likely benign (1x) and benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000528796	SCV001422736	benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Gln429Arg variant in GAA has been reported in one Taiwanese individual with glycogen storage disease II (PMID: 25466677). This variant has also been reported in ClinVar as benign by EGL Genetic Diagnostics and Invitae, and as likely benign by GeneDx (VariantID: 284497). This variant has been identified in 1.03% (196/19070) of East Asian chromosomes, 0.03% (1/29316) of South Asian chromosomes, and 0.002% (2/119604) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200294882). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. 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. This variant was found in cis with another pathogenic variant, suggesting that it may not cause disease (PMID: 25466677; Variation ID: 423925). In summary, this variant meets criteria to be classified as benign for glycogen storage disease II in an autosomal recessive manner based on its high frequency in the general population and the presence of the same amino acid in other mammals. ACMG/AMP Criteria applied: BA1, BP2, BP4 (Richards 2015).
Ambry Genetics	RCV002379127	SCV002691516	likely benign	Cardiovascular phenotype	2020-12-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.