Submissions for variant NM_000152.5(GAA):c.482_483del (p.Pro161fs)

dbSNP: rs764750389

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001219022	SCV001443288	pathogenic	Glycogen storage disease, type II	2020-11-02	reviewed by expert panel	curation	This variant, c.482_483del (p.Pro161GlnfsTer15), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and lack of gene product, meeting PVS1. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001836 in the European non-Finnish population, meeting PM2. Five individuals have been reported with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4. Of these individuals, three are compound heterozygous for c.-32-13T>G (PMID 9196050, 26873529), one is compound heterozygous for c.-32-3C>A (PMID 21550241; a patient with a similar description is reported in PMIDs 30155607, 21803581), and the second variant was unidentified in the remaining patient (PMID 9196050). The phase of the variants is unknown in these cases. The in trans data for the patient who is compound heterozygous for c.-32-3C>A will be used in the assessment of that variant and was not included here in order to avoid a circular argument. Therefore, PM3_Supporting is met. Additional patients have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) or full HGVS nomenclature was not provided (PMIDs 11071489, 28648663, 32248831). There is a ClinVar entry for this variant (Variation ID: 596146, 1 star review status) with one submitter classifying the variant as 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, PM2, PM3_Supporting, PP4.
Eurofins Ntd Llc (ga)	RCV000731885	SCV000859753	pathogenic	not provided	2018-02-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001219022	SCV001390942	pathogenic	Glycogen storage disease, type II	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro161Glnfs*15) 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 present in population databases (rs764750389, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with Pompe disease (PMID: 9196050, 26873529, 28648663). ClinVar contains an entry for this variant (Variation ID: 596146). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000731885	SCV002021182	pathogenic	not provided	2020-02-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001219022	SCV002051003	pathogenic	Glycogen storage disease, type II	2021-12-01	criteria provided, single submitter	clinical testing	Variant summary: GAA c.482_483delCC (p.Pro161GlnfsX15) 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 allele was found at a frequency of 8.2e-06 in 245102 control chromosomes (gnomAD). c.482_483delCC has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (Nicolino_1997, Stepien_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001219022	SCV004197881	pathogenic	Glycogen storage disease, type II	2023-12-28	criteria provided, single submitter	clinical testing