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

gnomAD frequency: 0.00002  dbSNP: rs104894833

Total submissions: 12

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.
Eurofins Ntd Llc (ga)	RCV000728539	SCV000856129	uncertain significance	not provided	2017-08-07	criteria provided, single submitter	clinical testing
Invitae	RCV000822343	SCV000963143	uncertain significance	Fabry disease	2022-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 66 of the GLA protein (p.Glu66Gln). This variant is present in population databases (rs104894833, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with classic, non-classic, and late onset Fabry disease and/or hypertrophic cardiomyopathy and renal failure without accumulation of Gb-3 or lysosomal deposits reported on renal or cardiac biopsy (PMID: 1315715, 7575533, 11137837, 20505683, 22874111, 23146289, 26179544, 26456105, 27160240). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 163548). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect GLA function (PMID: 22305854, 26179544). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	2023-03-09	criteria provided, single submitter	clinical testing	Variant summary: 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 0.0023 in 249895 control chromosomes, predominantly at a frequency of 0.008 within the Japanese subpopulation, and including at least 88 hemizygous males and 3 homozygous females (gnomAD v2, Lee_2010, jMorp database, Tadaka_2021). The observed variant frequency within the Japanese subpopulation is approximately 1.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in GLA causing Fabry disease (0.005) in control chromomes, suggesting that the variant is benign. 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 in two hemizygous brothers with suspected cardiac Fabry disease (Yoshitama_2001) and also 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 these findings. 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. Eight ClinVar submitters (evaluation after 2014) have cited the variant, 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=5; VUS, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance and may be associated with risk for late-onset, non-classic presentations of Fabry disease among individuals of East Asian ethnicities.
Illumina Laboratory Services, 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 Diagnostics, LLC DBA Color Health	RCV000822343	SCV001349224	likely benign	Fabry disease	2019-01-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000822343	SCV002054824	likely benign	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
3billion	RCV000822343	SCV002540759	likely benign	Fabry disease	2022-05-22	criteria provided, single submitter	clinical testing	This variant is observed at a frequency of 0.148% within East Asian subpopulation with 5 hemizygous male in gnomAD v2.1.1 dataset (BS1_S, BS2_S, total allele frequency: 0.01%). Missense variant of GLA gene is a common mechanism associated with Fabry disease (PP2_P). In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (PP3_P, 3CNET: 0.990, REVEL: 0.926). Therefore, this variant is classified as likely benign according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV003162613	SCV003911415	uncertain significance	Cardiovascular phenotype	2022-11-04	criteria provided, single submitter	clinical testing	The p.E66Q variant (also known as c.196G>C), located in coding exon 2 of the GLA gene, results from a G to C substitution at nucleotide position 196. The glutamic acid at codon 66 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in an individual with classical Fabry disease; however, he was also identified to have an additional alteration in GLA (Ishii S et al. Hum Genet, 1992 Apr;89:29-32). Additionally, this alteration was detected in several individuals with concerns for late onset Fabry disease (Yoshitama T et al. Am J Cardiol, 2001 Jan;87:71-5; Nakao S et al. Kidney Int, 2003 Sep;64:801-7; Shimotori M et al. Hum Mutat, 2008 Feb;29:331; Nakamura K et al. J Hum Genet, 2010 Apr;55:259-61; Lee BH et al. J Hum Genet, 2010 Aug;55:512-7; Kobayashi M et al. Mol Genet Metab, 2012 Dec;107:711-5; Doi K et al. J Hum Genet, 2012 Sep;57:575-9; Tomizawa Y et al. Intern Med, 2015 Oct;54:2503-6; Satomura A et al. Intern Med, 2015 Jul;54:1819-24; Oikawa M et al. BMC Cardiovasc Disord, 2016 May;16:83; Sakuraba H et al. Mol Genet Metab Rep, 2018 Dec;17:73-79; Kinoshita N et al. J Stroke Cerebrovasc Dis, 2018 Dec;27:3563-3569; Kim WS et al. J Korean Med Sci, 2019 Feb;34:e63). In vitro studies showed this alteration may not impact protein function (Hwu WL et al. Hum Mutat, 2009 Oct;30:1397-405; Park JY et al. Exp Mol Med, 2009 Jan;41:1-7). Based on data from gnomAD, the C allele has an overall frequency of 0.0108% (22/204601) total alleles studied, with 5 hemizygote(s) observed. The highest observed frequency was 0.1480% (22/14865) of East Asian alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000728539	SCV004235155	uncertain significance	not provided	2023-07-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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