Submissions for variant NM_000169.3(GLA):c.1255A>G (p.Asn419Asp)

dbSNP: rs879254061

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236612	SCV000293343	uncertain significance	not provided	2018-06-07	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the GLA gene. The N419D variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The N419D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics	RCV002418040	SCV002680894	uncertain significance	Cardiovascular phenotype	2020-05-08	criteria provided, single submitter	clinical testing	The p.N419D variant (also known as c.1255A>G), located in coding exon 7 of the GLA gene, results from an A to G substitution at nucleotide position 1255. The asparagine at codon 419 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001835738	SCV003477524	uncertain significance	Fabry disease	2024-08-01	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 419 of the GLA protein (p.Asn419Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 32843101). ClinVar contains an entry for this variant (Variation ID: 246044). 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 GLA protein function with a negative predictive value of 95%. 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.
Revvity Omics, Revvity	RCV000236612	SCV003816830	uncertain significance	not provided	2021-09-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150142	SCV003838818	uncertain significance	Cardiomyopathy	2021-09-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001835738	SCV002081327	uncertain significance	Fabry disease	2021-03-18	no assertion criteria provided	clinical testing