Submissions for variant NM_000152.5(GAA):c.2560C>T (p.Arg854Ter) (rs121907943)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255539	SCV000321686	pathogenic	not provided	2018-08-22	criteria provided, single submitter	clinical testing	The R854X pathogenic variant in the GAA gene has been reported previously in multiple individualswith glycogen storage disease type II in the homozygous state, as well as in the heterozygous state inthe presence of a second GAA variant (Bernstein et al., 2010; Burrow et al., 2010; Abbott et al., 2011;Palermo et al., 2012). Additionally, functional studies in COS cells with the R854X variant show thatthis variant impacts the function of the protein (Hermans et al., 1993). This variant is predicted tocause loss of normal protein function either through protein truncation or nonsense-mediated mRNAdecay. Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Projectreports that R854X was observed in 0.23%, 10/4406 alleles, from individuals of African Americanbackground, indicating it may be a rare variant in this population. We interpret R854X as apathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000255539	SCV000331031	pathogenic	not provided	2017-12-20	criteria provided, single submitter	clinical testing
Invitae	RCV000004249	SCV000626581	pathogenic	Glycogen storage disease, type II	2018-12-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal at codon 854 (p.Arg854*) of the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic. This particular variant has been reported as homozygous and as compound heterozygous in multiple individuals affected with glycogen storage disease type II (PMID: 9529346, 19588081, 17723315). ClinVar contains an entry for this variant (Variation ID: 4034). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America	RCV000004249	SCV000695654	pathogenic	Glycogen storage disease, type II	2016-09-29	criteria provided, single submitter	clinical testing	Variant summary: The GAA c.2560C>T (p.Arg854X) variant results in a premature termination codon, predicted to cause a truncated or absent GAA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 25/116512 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.002243 (23/10254). These frequencies are lower than the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), but suggest that this variant is of African origin. The variant has been identified in homozygous and compound heterozygous state in patients with Pompe disease, suggesting the variant is causative. Additionally, functional studies indicate that the variant has negligible catalytic activity and that the variant results in a transcript that is either not expressed or unstable. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000004249	SCV000893478	pathogenic	Glycogen storage disease, type II	2018-10-31	criteria provided, single submitter	clinical testing
OMIM	RCV000004249	SCV000024415	pathogenic	Glycogen storage disease, type II	1998-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000004249	SCV000086728	pathologic	Glycogen storage disease, type II	2013-05-09	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Counsyl	RCV000004249	SCV000485153	pathogenic	Glycogen storage disease, type II	2016-03-08	no assertion criteria provided	clinical testing