Submissions for variant NM_000152.5(GAA):c.1438-1G>C

dbSNP: rs147804176

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000169615	SCV001371774	pathogenic	Glycogen storage disease, type II	2020-05-04	reviewed by expert panel	curation	The c.1438-1G>C variant alters the canonical acceptor splice site of intron 9 and is predicted to impact splicing, possibly causing skipping of exon 10 which would result in an in frame deletion that removes ~4% of the primary amino acid sequence, including part of the GAA catalytic barrel (PMIDs 1856189; 22253258; DOI 10.1101/212837). However, in silico splicing predictors indicate the presence of a strong acceptor site 15 nucleotides upstream of the normal site which could be used in the absence of the normal site (Human Splicing Finder score for the normal site is 90.43, and for the upstream site the score is 88.06; MaxEnt Scan score for the normal site is 6.83, and for the upstream site it is 6.94). If the upstream site is used, this would result in the insertion of 5 amino acids and presence of the normal exon 10 sequence. To our knowledge, no functional analysis has been performed to determine the impact of this specific variant. However, the strength of PVS1 has been reduced to PVS1_Strong to recognize impact on the protein suggested by in silico predictors. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00011 in the African population, meeting PM2. Two patients with Pompe disease and meeting the ClinGen LSD VCEP's specifications for PP4 have been identified. One patient is compound heterozygous for the variant and c.1655T>C, phase unknown (p.Leu552Pro)(PMIDs 22538254). The second patient was identified in a clinical laboratory and is compound heterozygous for the variant and c.-32-13T>G, phase unknown. This data meets PM3. Pseudodeficiency variants are known to be absent in the second individual and, therefore, PP4_Moderate can be applied. Additional cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 27896092, 25455803), or HGVS nomenclature was not used (PMID 24495340). There is a ClinVar entry for this variant (Variation ID: 189184, 2 star review status) for which two submitters classify the variant as pathogenic, and one as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PVS1_Strong, PM2, PM3, PP4_Moderate.
Counsyl	RCV000169615	SCV000221141	likely pathogenic	Glycogen storage disease, type II	2015-02-18	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000727411	SCV000708298	pathogenic	not provided	2017-05-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169615	SCV000948372	pathogenic	Glycogen storage disease, type II	2023-08-20	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individuals with infantile-onset and adult-onset autosomal recessive Pompe disease (PMID: 22538254, 24495340, 25455803, 29122469). This variant is also known as IVS9-1G>C. ClinVar contains an entry for this variant (Variation ID: 189184). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant is present in population databases (rs147804176, gnomAD 0.01%). This sequence change affects an acceptor splice site in intron 9 of the GAA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169615	SCV001338646	pathogenic	Glycogen storage disease, type II	2020-04-20	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1438-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250786 control chromosomes. c.1438-1G>C has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease- examples Raben_2002, Prater_2012, Katona_2014, Vill_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, there is no experimental evidence evaluating an impact on protein function reported in the literature. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169615	SCV001422604	likely pathogenic	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The heterozygous c.1438-1G>C variant in GAA has been reported in at least 4 individuals (including 2 Caucasians) with Glycogen Storage Disease II (PMID: 11949932, 22538254, 24495340, 25455803), and has also been reported pathogenic by EGL and likely pathogenic by Counsyl in ClinVar (Variation ID: 189184). This variant has been identified in 0.012% (1/8698) of African chromosomes by the Genome Aggregation Database genomes (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs147804176) and had low quality. However, this variant was absent from large population studies for gnomAD exomes. Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal protein. There is an in-frame cryptic splice site 15 bases from the intron-exon boundary, providing evidence that this variant may add 5 amino acids instead of causing loss of function. However, this information is not predictive enough to determine pathogenicity. 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 combination with a pathogenic variant, and in individuals with Glycogen Storage Disease slightly increases the likelihood that the c.1438-1G>C variant is pathogenic (PMID: 22538254). The phenotype of two individuals heterozygous for this variant is highly specific for Glycogen Storage Disease II with abnormally low GAA activity detected in relevant tissues (PMID: 22538254, 24495340). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_supporting, PVS1_strong, PM2, PP4 (Richards 2015).
Revvity Omics, Revvity	RCV000727411	SCV002023825	pathogenic	not provided	2020-02-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169615	SCV002784836	pathogenic	Glycogen storage disease, type II	2021-07-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169615	SCV004195466	pathogenic	Glycogen storage disease, type II	2023-10-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169615	SCV004848317	pathogenic	Glycogen storage disease, type II	2024-04-15	criteria provided, single submitter	clinical testing	The c.1438-1G>C variant in GAA has been reported in at least 4 individuals with Pompe disease (Kroos 2008 PMID: 18425781, Prater 2012 PMID: 22538254, Vill 2015 PMID: 25455803), who had reduced GAA enzymatic activity. It has also been identified in 0.007% (5/74922) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. However, exon 10, which is impacted by the variant, is in frame and encodes less than 10% of the GAA protein, including part of an important catalytic domain in GAA (PMID: 1856189. Moreover, in silico splicing predictors indicate the presence of a strong acceptor site 15 nucleotides upstream of the normal site which could be used in the absence of the normal site. If used, this would result in the insertion of 5 amino acids and presence of the normal exon 10 sequence. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pompe disease. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PM2_Supporting, PP4.
Natera, Inc.	RCV000169615	SCV002092034	pathogenic	Glycogen storage disease, type II	2020-08-10	no assertion criteria provided	clinical testing