Submissions for variant NM_000152.5(GAA):c.1352C>G (p.Pro451Arg)

gnomAD frequency: 0.00133  dbSNP: rs7215458

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000546554	SCV001371748	likely benign	Glycogen storage disease, type II	2020-04-20	reviewed by expert panel	curation	This variant, c.1352C>G (p.Pro451Arg), has not been reported in the literature in any individuals with Pompe disease, and no results of functional studies are available, to our knowledge. The variant was reported in a patient with limb-girdle muscle weakness but was not thought to be causative of the symptoms (PMID 29149851). The highest population minor allele frequency in gnomAD v.2.1.1 is 0.00488 in the African population, meeting BS1. The score for the REVEL in silico meta-predictor is 0.449, suggesting that the variant does not impact GAA function, meeting BP4. There is a ClinVar entry for this variant (Variation ID: 281330) for which both submitters classify the variant as likely benign. In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BS1, BP4.
Eurofins Ntd Llc (ga)	RCV000370406	SCV000332073	likely benign	not specified	2016-01-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546554	SCV000626509	likely benign	Glycogen storage disease, type II	2025-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001576441	SCV001803631	likely benign	not provided	2021-02-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000546554	SCV002795338	likely benign	Glycogen storage disease, type II	2021-12-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000546554	SCV004563913	likely benign	Glycogen storage disease, type II	2023-01-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004992143	SCV005591971	uncertain significance	Cardiovascular phenotype	2024-08-23	criteria provided, single submitter	clinical testing	The p.P451R variant (also known as c.1352C>G), located in coding exon 8 of the GAA gene, results from a C to G substitution at nucleotide position 1352. The proline at codon 451 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a limb girdle muscular dystrophy cohort and an autism spectrum disorder cohort (Johnson K et al. Orphanet J Rare Dis, 2017 Nov;12:173; Tuncay IO et al. Cell Genom, 2023 Jul;3:100322). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Natera, Inc.	RCV000546554	SCV002092015	likely benign	Glycogen storage disease, type II	2021-02-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003939937	SCV004747873	likely benign	GAA-related disorder	2020-02-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).