ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1438-1G>C (rs147804176)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen 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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727411 SCV000708298 pathogenic not provided 2017-05-02 criteria provided, single submitter clinical testing
Invitae RCV000169615 SCV000948372 pathogenic Glycogen storage disease, type II 2020-02-15 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 of the GAA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with infantile-onset and adult-onset autosomal recessive Pompe disease (PMID: 29122469, 25455803, 22538254, 24495340). This variant is also known as IVS9-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 189184). Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.
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 Institute Rare Disease Group, Broad Institute RCV000169615 SCV001422604 likely pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided 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).

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