ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.196G>C (p.Glu66Gln) (rs104894833)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000150750 SCV000728500 likely benign not specified 2017-04-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000728539 SCV000856129 uncertain significance not provided 2017-08-07 criteria provided, single submitter clinical testing
Invitae RCV000822343 SCV000963143 uncertain significance Fabry disease 2019-04-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 66 of the GLA protein (p.Glu66Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs104894833, ExAC 0.2%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed to segregate with late-onset Fabry disease in several families (PMID: 26456105, 11137837) and has been observed in individuals affected with Fabry disease, some of whom had late-onset, mild, or non-classic disease or another variant in GLA (PMID: 1315715, 22874111, 20505683, 7575533, 11137837). This variant has also been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 27160240) and renal failure without accumulation of Gb-3 or lysosomal deposits reported on renal or cardiac biopsy (PMID: 26179544, 23146289). ClinVar contains an entry for this variant (Variation ID: 10723, 163548). Experimental studies have shown that this missense change decreases GLA activity but retains some residual enzyme activity (PMID: 17555407, 18205205, 10845698). 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.
Mendelics RCV000822343 SCV001141982 likely benign Fabry disease 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000150750 SCV001146953 uncertain significance not specified 2020-01-22 criteria provided, single submitter clinical testing GLA c.196G>C (p.Glu66Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 183742 control chromosomes, exclusively at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in GLA causing Fabry Disease, allowing no conclusion about variant significance. c.196G>C has been reported in the literature in sequencing studies of individuals affected with a variety of Fabry disease related phenotypes. A comprehensive review of literature spanning over two decades identified its occurrence in patients with reported/suspected diagnosis of Fabry disease (example, Ishii_1992, Park_2009, Lee_2010, Shimotori_2007, Sakuraba_2018), cohorts of male hemodialysis patients (Doi_2012, Maruyama_2013), patients on maintenance dialysis (Nishino_2012), male ischemic stroke (Nakamura_2013, Nagamatsu_2017) and newborn screening (Hwu_2009). It has also been observed in at least one case control study of patients with chronic kidney disease in whom no association with disease progression was identified (Watanabe_2015). Examples of isolated case reports of patients with this variant include, cerebral hemorrhage (Nakamura_2010), hemodialysis (Kikumoto_2012), a male with interstitial Nephritis and no pathological or cellular characteristics of Fabry disease (Satomura_2015), a male with suspected Fabry disease due to end stage renal failure and cardiomegaly in whom no pathological characteristics of Fabry were identified (Kobayashi_2012) and Parkinsonism without classic symptoms of Fabry (Tomizawa_2015). Notably many studies ascertained above also reported this variant in patients with normal levels of lyso Gb3, a common biomarker for Fabry disease (example, Sakuraba_2018). The variant was reported to co-segregate with the phenotype of chronic glomerulonephritis in one large Chinese family (Peng_2016). Additional reports of similar co-segregation in other kindreds will help corroborate this finding. In summary, these reports do not provide evidence for an unequivocal association of this variant with the phenotype of classic Fabry disease. At least one reported co-occurrence in cis with another pathogenic variant in the GLA gene in a male patient with classic Fabry disease has been reported (GLA c.334C>T, p.Arg112Cys), providing supporting evidence for a benign role (Ishii_1992). Several publications report experimental evidence evaluating an impact on protein function with variable findings on GLA enzyme activities in-vitro in transfected cells and patient leukocytes. The most pronounced variant effect results in less than 10% activity in some studies (example, Peng_2016, patient leukocytes),but 30%-50% of normal activity in many others (example, Park_2009, Shimotori_2007, Hwu_2009 in transfected cells). Furthermore, at least one in-vitro study evaluating kinetic parameters reported some instability at a neutral pH of 7.5 (reflective of the environment in the ER lumen) despite no impact on the enzyme kinetic properties at pH 4.5 (example, Ishii_2007). Therefore, given the wide variability in reported activities across a cross section of studies evaluated, an exact in-vivo impact of these findings on the associated pathophysiology of Fabry disease is not apparent. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, at-least one of whom reported other distinct and separate publications from those summarized above. These submitters reported the variant with conflicting assessments (likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic in association with risk for non-classic presentations of Fabry disease among individuals of East Asian ethnicities.
Illumina Clinical Services Laboratory,Illumina RCV000822343 SCV001327856 uncertain significance Fabry disease 2017-04-27 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.
Color Health, Inc RCV000822343 SCV001349224 likely benign Fabry disease 2019-01-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000150750 SCV000198201 uncertain significance not specified 2013-02-11 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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