Submissions for variant NM_000152.5(GAA):c.2307G>C (p.Leu769Phe)

dbSNP: rs372800172

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000295389	SCV000407294	uncertain significance	Glycogen storage disease, type II	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000295389	SCV000626561	uncertain significance	Glycogen storage disease, type II	2022-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 769 of the GAA protein (p.Leu769Phe). This variant is present in population databases (rs372800172, gnomAD 0.006%). 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: 325791). 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 not 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.
Genome-Nilou Lab	RCV000295389	SCV002027302	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002429282	SCV002731803	uncertain significance	Cardiovascular phenotype	2022-04-04	criteria provided, single submitter	clinical testing	The p.L769F variant (also known as c.2307G>C), located in coding exon 15 of the GAA gene, results from a G to C substitution at nucleotide position 2307. The leucine at codon 769 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV003133223	SCV003816203	uncertain significance	not provided	2021-03-08	criteria provided, single submitter	clinical testing
GeneDx	RCV003133223	SCV004036816	uncertain significance	not provided	2023-09-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc.	RCV000295389	SCV002092124	uncertain significance	Glycogen storage disease, type II	2019-11-11	no assertion criteria provided	clinical testing