Submissions for variant NM_000152.5(GAA):c.2736G>A (p.Ala912=)

gnomAD frequency: 0.00026  dbSNP: rs142472738

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726791	SCV000524733	likely benign	not provided	2020-07-13	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000726791	SCV000703073	uncertain significance	not provided	2016-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV001088082	SCV000752105	likely benign	Glycogen storage disease, type II	2024-01-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001088082	SCV001287987	uncertain significance	Glycogen storage disease, type II	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001088082	SCV001422613	likely benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.2736G>A (p.Ala912=) 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 Invitae and GeneDx in ClinVar (Variation ID: 384066). This variant has been identified in 0.028% (7/24932) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142472738). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. 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: PM2, BP4, BP7 (Richards 2015).
Genome-Nilou Lab	RCV001088082	SCV001810202	uncertain significance	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002436291	SCV002747595	likely benign	Cardiovascular phenotype	2020-03-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Natera, Inc.	RCV001088082	SCV002094484	likely benign	Glycogen storage disease, type II	2020-02-05	no assertion criteria provided	clinical testing