Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000525765 | SCV002583368 | uncertain significance | Glycogen storage disease, type II | 2022-09-19 | reviewed by expert panel | curation | The NM_000152.5:c.2132_2133delinsGG variant in GAA is a multinucleotide variant predicted to cause substitution of threonine by arginine at amino acid 711 (p.Thr711Arg). The same amino acid change, resulting from one of the two nucleotide changes observed in this multinucleotide variant, c.2132C>G, has been reported in a patient with Pompe disease (PMID: 20080426, 31342611). However, this other variant has conflicting evidence for pathogenicity based on guidelines by the ClinGen LSD VCEP (PMID: 18425781). The minor allele frequency of the c.2132C>G variant in gnomAD v2.1.1 is 0.001258 (23/18290 alleles) in the East Asian population, but was only seen in phase with c.2133A>G in 23 of the 24 heterozygotes reported in gnomAD v2.1.1. Therefore, the highest possible population minor allele frequency in gnomAD v2.1.1 is 0.001258 (23/18290 alleles) in the East Asian population (none of the population data codes are met). The computational predictors PROVEAN, Mutation Taster, and MutPredIndel suggest that this variant has a deleterious effect on the GAA gene, evidence that correlates with impact to GAA function (PP3). To our knowledge, the results of functional assays have not been reported for this variant. There is a ClinVar entry for this variant (Variation ID: 456391, 1 star review status) with 2 submitters, 1 submitter classifying the variant as likely pathogenic and 1 submitter classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3. |
| Labcorp Genetics |
RCV000525765 | SCV000626545 | likely pathogenic | Glycogen storage disease, type II | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 711 of the GAA protein (p.Thr711Arg). This variant is present in population databases (no rsID available, gnomAD 0.009%). A different variant (c.2132C>G) giving rise to the same protein effect has been determined to be pathogenic (PMID: 18211760, 23884227, 28394184). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 456391). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Mayo Clinic Laboratories, |
RCV001507905 | SCV001713744 | uncertain significance | not provided | 2021-01-12 | criteria provided, single submitter | clinical testing |