Submissions for variant NM_000152.5(GAA):c.1193del (p.Leu398fs)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000410060	SCV001443333	likely pathogenic	Glycogen storage disease, type II	2023-03-10	reviewed by expert panel	curation	The NM_000152.5:c.1193del (p.Leu398ArgfsTer42) 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). This variant is not in gnomAD v2.1.1. (PM2_Supporting). This variant has been reported in one patient with POmpe disease; however residual GAA activity was not provided and the second variant is not reported (PMID 30155607). There is a ClinVar entry for this variant (Variation ID: 371457). The classification of this variant has been upgraded from Variant of Uncertain Significance to Likely Pathogenic based on the recommendations of the ClinGen Sequence Variant Interpretation Working Group, that a variant meeting PVS1 and PM2_Supporting is classified as Likely Pathogenic (https://clinicalgenome.org/site/assets/files/5182/pm2_-_svi_recommendation_-_approved_sept2020.pdf ). In summary, this variant meets the criteria to be classified as likely pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): PVS1, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP, March 10, 2023).
Counsyl	RCV000410060	SCV000487046	likely pathogenic	Glycogen storage disease, type II	2016-09-30	criteria provided, single submitter	clinical testing
Invitae	RCV000410060	SCV000816104	pathogenic	Glycogen storage disease, type II	2023-04-26	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371457). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 30155607). This sequence change creates a premature translational stop signal (p.Leu398Argfs*42) 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).
Fulgent Genetics, Fulgent Genetics	RCV000410060	SCV002799933	pathogenic	Glycogen storage disease, type II	2021-07-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000410060	SCV004197885	likely pathogenic	Glycogen storage disease, type II	2022-10-31	criteria provided, single submitter	clinical testing

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