Submissions for variant NM_000152.5(GAA):c.2140del (p.His714fs)

dbSNP: rs786204549

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000169264	SCV001371739	pathogenic	Glycogen storage disease, type II	2020-02-14	reviewed by expert panel	curation	This variant, c.2140delC (p.His714Thrfs), is a frameshift variant that is predicted to result in a premature termination codon, nonsense mediated decay, and no gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. This variant has been reported in two patients who also carry a second variant in GAA. One of these cases meets the ClinGen LSD VCEP's specifications for PP4 and is compound heterozygous for p.His714Thrfs and a missense variant, c.1561G>A (p.Glu521Lys); the phase is unknown (PMID 17723315). The in trans data from this patient will be used in the assessment of p.Glu521Lys and, therefore, was not included here in order to avoid circular logic. The second case is compound heterozygous for the variant and c.-32-13T>G (PMID 30564623) but the GAA activity was not reported and PP4 cannot be assessed. There is a ClinVar entry for this variant (Variation ID: 188904, 2 star review status) with 2 submtters classifying the variant as pathogenic and one as likely 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, PP4.
Counsyl	RCV000169264	SCV000220555	likely pathogenic	Glycogen storage disease, type II	2014-07-25	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000725052	SCV000333554	pathogenic	not provided	2015-08-12	criteria provided, single submitter	clinical testing
Invitae	RCV000169264	SCV000626534	pathogenic	Glycogen storage disease, type II	2022-08-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188904). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 17723315). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His714Thrfs*50) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169264	SCV001431949	pathogenic	Glycogen storage disease, type II	2020-08-17	criteria provided, single submitter	clinical testing	Variant summary: GAA c.2140delC (p.His714ThrfsX50) 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 223082 control chromosomes. c.2140delC has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease, McCready_2007, Nallamilli_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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.
Baylor Genetics	RCV000169264	SCV004197828	pathogenic	Glycogen storage disease, type II	2023-05-24	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169264	SCV002092101	pathogenic	Glycogen storage disease, type II	2021-05-10	no assertion criteria provided	clinical testing