Submissions for variant NM_000152.5(GAA):c.917C>T (p.Ser306Leu)

gnomAD frequency: 0.00292  dbSNP: rs138097673

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178719	SCV000230858	benign	not specified	2014-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000178719	SCV000247444	uncertain significance	not specified	2014-04-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000178719	SCV000302702	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV001704853	SCV000521135	likely benign	not provided	2021-03-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22252923)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545994	SCV000626655	benign	Glycogen storage disease, type II	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000545994	SCV001285462	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	RCV000545994	SCV001422935	likely benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The heterozygous p.Ser306Leu variant in GAA has been reported in 1 African American individual with Glycogen Storage Disease II (PMID: 22252923) and has been identified in 0.9373% (228/24326) of African chromosomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs138097673). 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. This variant has also been reported as a benign variant (by Invitae and EGL), likely benign variant (by GeneDx and PreventionGenetics), and VUS (by University of Chicago) in ClinVar (Variation ID: 197633). 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. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4 (Richards 2015).
Genome-Nilou Lab	RCV000545994	SCV001810518	likely benign	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000178719	SCV002074273	likely benign	not specified	2022-01-15	criteria provided, single submitter	clinical testing	Variant summary: GAA c.917C>T (p.Ser306Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 245226 control chromosomes, predominantly at a frequency of 0.0091 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 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 or African-American origin. c.917C>T has been reported in the literature as a benign variant in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (example Bali_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as benign/likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc.	RCV000545994	SCV002091981	likely benign	Glycogen storage disease, type II	2020-01-17	no assertion criteria provided	clinical testing