Submissions for variant NM_000169.3(GLA):c.899T>C (p.Leu300Pro)

dbSNP: rs398123223

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723759	SCV000110140	pathogenic	not provided	2013-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000078300	SCV000695751	pathogenic	Fabry disease	2016-03-08	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a conserved nucleotide an results in a replacement of a Leucine (L) with a Proline (P). 5/5 in silico tools predict the variant to be disease causing. The variant is absent from the large and broad cohorts of the ExAC project but was reported in several Fabry patients (Benjamin_JIMD_200; Wu_HM_2011, Lenders_Neurology_2015) indicating pathogenicity. Several independent publications report the variant to result in loss of -Gal A Activity, further supporting a deleterious outcome (Benjamin_JIMD_2009; Shin_Biochem Biophys Res Commun_2007; Wu_HM_2011). Of note, in the presence of DGJ (DGJ, migalastat hydrochloride, AT1001)) -Gal A activity increased 36 times in T cells derived from variant carrier patients (Shin_Biochem Biophys Res Commun_2007) suggesting that patients with the variant of interest migh benefit from DGJ therapy. Additionally, a reputable data base and ClinVar lists variant as pathogenic. Moreover, HGMD lists variants affecting the same codon (c.899T>A, p.Leu300His; c. c.898C>T, p.Leu300Phe) as pathogenic, indicating the variant to be located in a mutational hotspot and suggesting a particular functional importance of the Leu300 residue. Considering all evidence, the variant was classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000078300	SCV001216767	pathogenic	Fabry disease	2023-08-17	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 92569). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu300 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 22004918, 28728877), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GLA function (PMID: 21598360). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLA protein function. This missense change has been observed in individual(s) with Fabry disease (PMID: 18698230, 19387866). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 300 of the GLA protein (p.Leu300Pro).
Genome-Nilou Lab	RCV000078300	SCV002054800	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000078300	SCV001327852	uncertain significance	Fabry disease	2017-04-28	flagged submission	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.