Submissions for variant NM_000169.3(GLA):c.1192G>A (p.Glu398Lys)

gnomAD frequency: 0.00002  dbSNP: rs104894844

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514846	SCV000611048	uncertain significance	not provided	2017-09-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188455	SCV001355514	uncertain significance	Fabry disease	2019-09-26	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 398 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Fabry disease (PMID: 12175777). This variant has been identified in 2/205639 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV001188455	SCV002054339	uncertain significance	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001188455	SCV003274771	uncertain significance	Fabry disease	2022-06-14	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 398 of the GLA protein (p.Glu398Lys). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with GLA-related conditions (PMID: 12175777). ClinVar contains an entry for this variant (Variation ID: 446069). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV004023491	SCV005032797	uncertain significance	Cardiovascular phenotype	2023-12-14	criteria provided, single submitter	clinical testing	The p.E398K variant (also known as c.1192G>A), located in coding exon 7 of the GLA gene, results from a G to A substitution at nucleotide position 1192. The glutamic acid at codon 398 is replaced by lysine, an amino acid with similar properties. This variant has been reported in a Fabry disease cohort in a female (Shabbeer J et al. Mol Genet Metab, 2002 May;76:23-30; Shabbeer J et al. Hum Mutat, 2005 Mar;25:299-305). Additionally, an in vitro assay showed this variant has 63% enzyme activity compared to wild-type (Benjamin ER et al. Genet Med, 2017 Apr;19:430-438). Based on data from gnomAD, the A allele has an overall frequency of 0.0010% (2/205639) total alleles studied, with 1 hemizygote(s) observed. The highest observed frequency was 0.0022% (2/92832) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. 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.