ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1822C>T (p.Arg608Ter)

gnomAD frequency: 0.00001  dbSNP: rs749529161
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV001249049 SCV002032126 pathogenic Glycogen storage disease, type II 2021-10-26 reviewed by expert panel curation The NM_000152.5:c.1822C>T (p.Arg608Ter) variant in GAA is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 13/20, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This variant has been identified in a patient with no GAA cross reactive immunological material in skin fibroblasts supporting that it is a loss of function variant (PMIDs 22252923, 32849613)(PVS1). This variant has been detected in at least 13 individuals reported to have Pompe disease. At least 10 patients, mostly East Asian, have been reported with features with high specificity for Pompe disease including documentation of laboratory values showing deficient GAA activity and/or clinical features consistent with infantile onset Pompe disease and/or treated with enzyme replacement therapy, all meeting the specifications for PP4_Moderate (PMID 21484825, 21940687, 23884227, 24269976, 26693141, 29124014, 29422078, 30360039, 31439017, 31875618, 32849613). Of the individuals with this variant who are reported to have Pompe disease, two individuals were compound heterozygous for the variant and a pathogenic variant; in one case, the variant was confirmed in trans with c.2662G>T (p.Glu888Ter)(PMID 31743840, ClinVar SCV SCV001371767.1), and in another case the variant was found in compound heterozygosity, phase unknown, with c.-32-13T>G (PMID 31545528)(phase unknown). Another individual was homozygous for the variant (PMID 29124014)(PM3_Strong). In addition, the variant was found in compound heterozygosity with the following variants, phase unknown - c.1935C>A (p.Asp645Glu) (PMID 24269976, 31439017), c.875A>G (p.Tyr292Cys)(PMID 21940687, 23884227, 30360039), c.1309C>T (p.Arg437Cys)(PMID 21940687, 23884227, 30360039), c.784G>A (p.Glu262Lys)(PMID 29422078), c.2238G>C (p.Trp746Cys)(PMID 28433475), c.953T>A (p.Met318Lys)(PMID 21484825), and c.1754+2T>A (PMID 26693141, 32849613), and it was confirmed in trans with c.2297A>C (p.Tyr766Ser)(PMID 31875618). The allelic data from these additional patients will be used in the assessment of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population, which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variant ID: 972803, 1 star review status) with two submitters classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2): PVS1, PM3_Strong, PP4_Moderate, PM2_Supporting. Classification approved by the ClinGen LSD VCEP: Oct. 19th, 2021.
Broad Institute Rare Disease Group, Broad Institute RCV001249049 SCV001422994 pathogenic Glycogen storage disease, type II 2020-01-22 criteria provided, single submitter curation The p.Arg608Ter variant in GAA has been reported in at least 3 individuals with glycogen storage disease II (PMID: 26693141, 21484825, 18425781) and has been identified in 0.005% (1/19598) of East Asian chromosomes, 0.004% (1/24638) of European (Finnish) chromosomes, and 0.002% (3/125720) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs749529161). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 608, 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 phenotype of an individual compound heterozygous for this variant is highly specific for glycogen storage disease based on GAA activity being less than 1% of wild-type and the absence of pseudo-deficiency alleles, consistent with disease (PMID: 21484825). In summary, this variant meets criteria to be classified as pathogenic for glycogen storage disease II in an autosomal recessive manner based on the prediction that it causes loss of function, and its low frequency in the general population. ACMG/AMP Criteria applied: PVS1, PM2, PP4_moderate (Richards 2015).
Invitae RCV001249049 SCV001591284 pathogenic Glycogen storage disease, type II 2024-01-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg608*) in 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 (PMID: 18425781, 22252923). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with glycogen storage disease, type II (GSDII), also known as Pompe disease (PMID: 29422078, 31743840, 31875618). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 972803). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity Omics RCV001780194 SCV002023820 pathogenic not provided 2020-11-03 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001780194 SCV002563441 pathogenic not provided 2021-07-01 criteria provided, single submitter clinical testing
Baylor Genetics RCV001249049 SCV004197784 pathogenic Glycogen storage disease, type II 2023-07-26 criteria provided, single submitter clinical testing
Natera, Inc. RCV001249049 SCV002092067 pathogenic Glycogen storage disease, type II 2020-08-20 no assertion criteria provided clinical testing

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