Submissions for variant NM_000152.5(GAA):c.722_723del (p.Phe241fs)

dbSNP: rs2039116471

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001200871	SCV001371761	pathogenic	Glycogen storage disease, type II	2020-01-21	reviewed by expert panel	curation	This variant, c.722_723del (p.Phe241CysfsTer), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product. Therefore, PVS1 can be applied. This variant is absent in gnomAD v2.1.1, meeting PM2. It has been found in at least two patients with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4 (PMID 19775921). One of these patients is compound heterozygous for the variant and c.1687C>T (p.Gln563Ter), and the other is compound heterozygous for the variant and c.1754+1G>A. In both cases, the variants were confirmed to be in trans. This data meets PM3_Strong. Additional cases have been reported, but did not meet PP4 (PMID 28838325). There is no ClinVar entry for this variant. 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, PM2, PM3_Strong, PP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001200871	SCV002196654	pathogenic	Glycogen storage disease, type II	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe241Cysfs*88) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 11949932, 18425781). This variant is also known as c.721_722delTT. ClinVar contains an entry for this variant (Variation ID: 932903). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001200871	SCV002598558	pathogenic	Glycogen storage disease, type II	2022-09-26	criteria provided, single submitter	clinical testing	Variant summary: GAA c.722_723delTT (p.Phe241CysfsX88) 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. The variant was absent in 251118 control chromosomes. c.722_723delTT has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease; examples: Kishnani_2010, Bali_2012, Kroos_2008, etc). These data indicate that the variant is likely to be associated with disease. Two 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. Based on the evidence outlined above, the variant was classified as pathogenic.