ClinVar Miner

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

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Total submissions: 2
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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.

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