ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.239G>A (p.Gly80Asp) (rs781838005)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000209421 SCV000748699 uncertain significance Fabry disease 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 80 of the GLA protein (p.Gly80Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Fabry disease (PMID: 26415523). ClinVar contains an entry for this variant (Variation ID: 217380). Experimental studies have shown that this missense change decreases GLA enzyme activity in vitro (PMID: 26415523). 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000732705 SCV000860685 uncertain significance not provided 2018-03-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000993846 SCV000919435 uncertain significance not specified 2019-11-22 criteria provided, single submitter clinical testing Variant summary: GLA c.239G>A (p.Gly80Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several studies report this variant has an impact on protein function and results in decreasing alpha-Gal-A activity in transfected cells, plasma, isolated leukocytes (Lukas_2016, Frabasil_2019, Wasserstein_2019, Gupta_2019). The variant was absent in 183388 control chromosomes (gnomAD). c.239G>A was initially reported as a variant with mild reduction in alpha gal enzyme activity (29.3% of normal) and slightly elevated biomarker (lyso Gb3) values in a study of patients undergoing Fabry disease testing at a commercial laboratory (Lukas_2016). Subsequently, this variant was also reported in one SUD patient associated with cardiac disease (Lin_2017), an Argentinian male dialysis patient with non confirmed Fabry disease (Frabasil_2019), one unpublished case report of a patient with autism and learning diffculties but not clinically diagnosed with Fabry disease (Gupta_2019), and unaffected Eucadorian Hispanic infants in NY pilot NBS program not diagnosed with a personal or a family history of Fabry disease (Wasserstein_2019). As this variant is associated with significant residual enzyme activity and has a fairly high frequency in the admixed American population, the authors interpret it as likely benign (Wasserstein_2019). Since its initial evaluation as a likely pathogenic variant at our laboratory in 2017, two additional ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Due to additional recent reports of non association with classic Fabry disease despite a mild reduction in in-vitro enzyme activity as summarized above, this variant was re-classified as uncertain significance.
Albrecht-Kossel-Institute,Medical University Rostock RCV000209421 SCV000246033 likely pathogenic Fabry disease 2014-01-01 no assertion criteria provided research
Albrecht-Kossel-Institute,Medical University Rostock RCV000209815 SCV000246034 drug response Migalastat response 2014-01-01 no assertion criteria provided research
Natera, Inc. RCV000209421 SCV001458762 uncertain significance Fabry disease 2020-09-16 no assertion criteria provided clinical testing

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