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

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen	RCV000004249	SCV001371731	pathogenic	Glycogen storage disease, type II	2020-05-05	reviewed by expert panel	curation	This variant, c.2560C>T (p.Arg854Ter) is a nonsense variant that is predicted to result in a premature stop codon, nonsense mediated decay, and lack of gene product, meeting PVS1. This is supported by reports of numerous patients who are homozygous for the variant, or compound heterozygous for the variant and another loss of function variant, and who have absent GAA cross-reactive immunological material in cultured skin fibroblasts (i.e. CRIM-negative) (e.g. PMIDs 19775921, 21889385, 22237443, 22252923, 23601496, 2574186). In addition, expression of the variant in COS cells resulted in virtually no increase in activity compared to the negative control (PMID 8094613). This variant is the most commonly reported variant in individuals with infantile onset Pompe disease, especially in those of African descent (PMIDs 9529346, 22253258, 31342611). The highest population minor allele frequency is gnomAD v2.1.1 is 0.00189 in the African population. This variant been reported in numerous individuals with Pompe disease who meet the specifications of the ClinGen LSD VCEP for PP4. This includes homozygous individuals (e.g. PMIDs 17723315, 21889385, 23601496, 25741864, 26497565) and compound heterozygotes with another pathogenic variant in GAA such as c.-32-13G>T (PMID 17723315), c.525delT (PMID 23825616), c.1165delG (PMID 22252923), c.1654delC (PMID 25741864), c.1933G>A (p.Asp645Asn) (PMID 31193175), c.1655T>C (p.Leu552Pro)(PMID 31193175). This data meets PM3_Very Strong. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1, PM3_Very Strong, PP4.
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	2020-01-07	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
Myriad Women's Health, Inc.	RCV000004249	SCV001193985	pathogenic	Glycogen storage disease, type II	2019-12-20	criteria provided, single submitter	clinical testing	NM_000152.3(GAA):c.2560C>T(R854*) is classified as pathogenic in the context of Pompe disease. Sources cited for classification include the following: PMID 11071489, 19862843, 20472203, 22555271, 9529346, 16702877 and 8094613. Classification of NM_000152.3(GAA):c.2560C>T(R854*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000004249	SCV001251812	pathogenic	Glycogen storage disease, type II	2020-05-03	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000004249	SCV001364292	pathogenic	Glycogen storage disease, type II	2020-04-02	criteria provided, single submitter	research	ACMG codes: PVS1, PM3, PM3, PP5
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.
Broad Institute Rare Disease Group,Broad Institute	RCV000004249	SCV001422773	pathogenic	Glycogen storage disease, type II	2020-01-22	no assertion criteria provided	curation	The p.Arg854Ter variant in GAA has been reported in at least 66 individuals (including 13 African American, 10 Brazilian, 4 Columbian, 4 from the UK, 2 Caucasian, 1 French, 1 Omani, 1 Pakistani, and 1 Dominican/Caucasian individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 23430493, 19588081, 26497565, 9529346, 10528311, 16860134, 17723315, 21484825, 18535739, 11071489, 24273659, 23601496, 22237443, 21889385, 23825616, 29122469, 25741864, 19775921, 8094613), and has also been reported pathogenic (by GeneDx, EGL, Counsyl, Invitae, Integrated Genetics, Fulgent Genetics, OMIM, and GeneReviews) in ClinVar (Variation ID: 4034). This variant has been identified in 0.189% (47/24858) of African chromosomes and 0.020% (7/34802) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907943). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This nonsense variant leads to a premature termination codon at position 854, which is predicted to lead to a truncated or absent protein. Loss of function of the GAA gene is an established disease mechanism in autosomal recessive Glycogen Storage Disease II. The presence of this variant in the homozygous state and in combination with reported pathogenic variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Arg854Ter variant is pathogenic (PMID: 23430493, 19588081, 26497565, 9529346, 10528311, 16860134, 17723315, 21484825, 18535739, 11071489, 24273659, 23601496, 22237443, 21889385, 23825616, 29122469, 25741864, 19775921, 8094613). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on their CRIM-negative status and reduced GAA activity detected by assays of relevant tissues, consistent with disease (PMID: 26497565, 23601496, 22237443, 21889385, 11071489, 8094613, 16860134, 22237443, 21889385, 23825616, 29122469, 25741864, 19775921). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with pathogenic GAA variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PP4 (Richards 2015).