ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.899T>C (p.Leu300Pro) (rs398123223)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723759 SCV000110140 pathogenic not provided 2013-10-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000078300 SCV001216767 pathogenic Fabry disease 2020-01-13 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 300 of the GLA protein (p.Leu300Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Fabry disease (PMID: 18698230, 19387866). ClinVar contains an entry for this variant (Variation ID: 92569). This variant has been reported to affect GLA protein function (PMID: 21598360). 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. For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000078300 SCV001327852 uncertain significance Fabry disease 2017-04-28 criteria provided, single submitter 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.

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