Submissions for variant NM_000152.5(GAA):c.915G>A (p.Gly305=)

gnomAD frequency: 0.00113  dbSNP: rs150343359

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723389	SCV000330943	uncertain significance	not provided	2018-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000723389	SCV000525438	likely benign	not provided	2021-05-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22644586, 29149851)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079201	SCV000626654	likely benign	Glycogen storage disease, type II	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001079201	SCV001285461	uncertain significance	Glycogen storage disease, type II	2018-01-13	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	RCV001079201	SCV001423082	likely benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The c.915G>A (p.Gly305=) variant in GAA has been reported in 2 individuals with limb-girdle muscle weakness (PMID: 29149851) and has also been reported as a likely benign variant by GeneDx and Invitae and as a VUS by EGL in ClinVar (Variation ID: 188478). This variant has been identified in 0.1843% (232/125858) of European (non-Finnish) chromosomes and 0.1138% (40/35140) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150343359). Although this variant has been seen in the general population, its frequency is not 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. 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: BP4, BP7 (Richards 2015).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001079201	SCV001473234	likely benign	Glycogen storage disease, type II	2022-04-21	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001079201	SCV001712370	likely benign	Glycogen storage disease, type II	2021-05-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000723389	SCV001747890	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	GAA: BP4, BP7
Mayo Clinic Laboratories, Mayo Clinic	RCV000723389	SCV002541442	uncertain significance	not provided	2023-03-23	criteria provided, single submitter	clinical testing	BP4, BP7, PM3
Ambry Genetics	RCV002372058	SCV002685706	likely benign	Cardiovascular phenotype	2022-03-04	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.	RCV001079201	SCV001453420	likely benign	Glycogen storage disease, type II	2020-01-10	no assertion criteria provided	clinical testing