Submissions for variant NM_000152.5(GAA):c.2218G>A (p.Val740Met)

dbSNP: rs752122499

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558189	SCV000626553	uncertain significance	Glycogen storage disease, type II	2022-05-27	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 740 of the GAA protein (p.Val740Met). This variant is present in population databases (rs752122499, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 456395). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function. 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.
Illumina Laboratory Services, Illumina	RCV000558189	SCV001281476	uncertain significance	Glycogen storage disease, type II	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome-Nilou Lab	RCV000558189	SCV002027298	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002431531	SCV002728839	uncertain significance	Cardiovascular phenotype	2021-12-24	criteria provided, single submitter	clinical testing	The p.V740M variant (also known as c.2218G>A), located in coding exon 15 of the GAA gene, results from a G to A substitution at nucleotide position 2218. The valine at codon 740 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.