Submissions for variant NM_000152.5(GAA):c.1324G>A (p.Val442Met)

gnomAD frequency: 0.00001  dbSNP: rs377559348

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594193	SCV000701854	uncertain significance	not provided	2016-10-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000668689	SCV000793333	uncertain significance	Glycogen storage disease, type II	2017-08-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668689	SCV000935513	uncertain significance	Glycogen storage disease, type II	2022-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 442 of the GAA protein (p.Val442Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Pompe disease (PMID: 21232767). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 497377). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000668689	SCV001422810	uncertain significance	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Val442Met variant in GAA has been reported in 1 individual with Glycogen Storage Disease II in a newborn screening program in Taiwan (PMID: 21232767). This variant has been identified in 0.008% (1/12176) of African chromosomes and 0.002% (2/87210) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs377559348). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a VUS by Counsyl, Invitae, and EGL Genetic Diagnostics in ClinVar (Variation ID: 497377). In vitro functional studies provide some evidence that the p.Val442Met variant may not be pathogenic and result in a false-positive for Glycogen Storage Disease II screening in the presence of the known pseudodeficiency allele p.Gly576Ser (PMID: 23632029). The pseudodeficiency allele was seen in cis with the p.Val442Met variant in the proband discovered via newborn screening (PMID: 21232767). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant was reported in combination with a reported likely pathogenic variant, p.Gly615Arg, and in an individual with Glycogen Storage Disease II (Variation ID: 188786). In summary, the clinical significance of the p.Val442Met variant is uncertain. ACMG/AMP Criteria applied: PM2, BS3_Supporting (Richards 2015).
Genome-Nilou Lab	RCV000668689	SCV002027265	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000594193	SCV003828433	uncertain significance	not provided	2020-06-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000594193	SCV005434960	uncertain significance	not provided	2024-11-01	criteria provided, single submitter	clinical testing	GAA: PM2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000668689	SCV005879502	uncertain significance	Glycogen storage disease, type II	2024-08-22	criteria provided, single submitter	clinical testing	The GAA c.1324G>A; p.Val442Met variant (rs377559348, ClinVar Variation ID: 497377) is reported in the literature in an individual affected with late onset Pompe disease that also carried a pseudodeficiency variant in cis with p.Val442Met and another GAA variant in trans (Chien 2011). This variant is only observed on three alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.692). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Chien YH et al. Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. J Pediatr. 2011 Jun;158(6):1023-1027.e1. PMID: 21232767.
Natera, Inc.	RCV000668689	SCV001455611	uncertain significance	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing