Submissions for variant NM_000152.5(GAA):c.1951_1952delinsT (p.Gly651fs)

dbSNP: rs1567835781

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000781390	SCV001443293	pathogenic	Glycogen storage disease, type II	2023-06-27	reviewed by expert panel	curation	The NM_000152.5(GAA):c.1951_1952delinsT (p.Gly651SerfsTer45) variant in GAA is a frameshift variant predicted to cause a premature stop codon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). Two siblings with late onset Pompe disease are compound heterozygous for the variant and a pathogenic variant in GAA, c.-32-13T>G; phase unknown, and are treated with enzyme replacement therapy (PMID 31392188) (PP4). In addition, an adult patient with clinical symptoms consistent with Pompe disease, undergoing genetic testing in a clinical laboratory, is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP, c.2014C>T (p.Arg672Trp) (PM3). There is a ClinVar entry for this variant (Variation ID: 633225). 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 Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM3, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on June 27, 2023)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781390	SCV000919378	likely pathogenic	Glycogen storage disease, type II	2018-03-20	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1951_1952delinsT (p.Gly651SerfsX45) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.2188G>T, p.Glu730X; c.2544delC, p.Lys849fsX38). The variant was absent in 237910 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1951_1952delinsT in individuals affected with Pompe disease and no experimental evidence demonstrating its impact on protein function have been reported in the literature. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV001784394	SCV002023866	pathogenic	not provided	2019-07-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001784394	SCV002065854	likely pathogenic	not provided	2021-07-14	criteria provided, single submitter	clinical testing	DNA sequence analysis of the GAA gene demonstrated a sequence change, c.1951_1952delinsT, which occurs in exon 14 and results in an amino acid frameshift and the creation of a premature termination codon 45 amino acids downstream of the sequence change, p.Gly651Serfs*45. This sequence change is predicted to result in an abnormal, truncated GAA protein that is likely to be degraded and/or affect its normal function. This sequence change has not been described in the gnomAD database (dbSNP rs1567835781). This sequence change has been identified in the compound heterozygous state with the c.-32-13T>G pathogenic variant in two siblings with late-onset Pompe disease (PMID 31392188), however residual GAA activity was not provided. A similar variant (c.1952del, p.Gly651Alafs*45), has also been identified in compound heterozygous state with the c.-32-13T>G in an individual with late-onset Pompe disease (PMID: 31125121). Based on these evidences, the c.1951_1952delinsT variant is classified as likely pathogenic. Our interpretation is based on the current understanding of the genetics of GAA-related disorders.
Baylor Genetics	RCV000781390	SCV004195458	pathogenic	Glycogen storage disease, type II	2023-10-05	criteria provided, single submitter	clinical testing
Invitae	RCV000781390	SCV004536036	pathogenic	Glycogen storage disease, type II	2021-05-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly651Alafs*45) 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 not available, as this variant may be reported as separate entries in the ExAC database. For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with Pompe disease (PMID: 31392188). ClinVar contains an entry for this variant (Variation ID: 632822).