ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.352C>T (p.Arg118Cys) (rs148158093)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619869 SCV000736028 uncertain significance Cardiovascular phenotype 2017-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Blueprint Genetics RCV000723556 SCV000927454 uncertain significance not provided 2017-10-26 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769541 SCV000900937 uncertain significance Cardiomyopathy 2017-03-01 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000078277 SCV000503540 uncertain significance Fabry disease 2016-08-01 no assertion criteria provided research Found in a female patient having exome sequencing for an unrelated indication. No known history of Fabry disease.
Color RCV000078277 SCV000904642 uncertain significance Fabry disease 2018-08-13 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the GLA protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Experimental studies have shown that this variant may cause partially reduced alpha-Gal enzyme activity (20-30% wild-type activity) in mammalian cells (PMID: 23935525, 16773563). However, clinical significance of this finding is unknown. This variant has been reported in multiple individuals affected with late-onset Fabry disease (PMID: 20122163, 22551898, 25468652). This variant is not rare in the general population and has been identified in 43/200247 chromosomes by the Genome Aggregation Database (gnomAD). A study of 22 individuals of Portuguese and Spanish ancestry carrying this variant, including 3 homozygous females, has suggested that this variant does not appear to segregate with Fabry disease (PMID: 25468652). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723556 SCV000110117 likely pathogenic not provided 2018-01-11 criteria provided, single submitter clinical testing
GeneDx RCV000035303 SCV000207820 uncertain significance not specified 2017-10-26 criteria provided, single submitter clinical testing The R118C variant of uncertain significance in the GLA gene has been previously reported in association with both classical and late-onset Fabry disease (Spada et al., 2006; Gaspar et al., 2010; Baptista et al., 2010; Tucara et al., 2012; Pasqualim et al., 2014; Savary et al., 2017; Gonçalves et al., 2017; Nowak et al., 2017). However, the R118C variant has also been reported in patients who do not meet clinical criteria for a diagnosis of Fabry disease (Morais et al., 2008; Kilarski et al., 2015; de Greef et al., 2016) and in patients with cardiomyopathy who do not have other features of Fabry disease (Golbus et al., 2014; Caetano et al., 2014). Specifically, Golbus et al. (2014) identified R118C in conjunction with a second variant in TMP1 in a patient with DCM who required a heart transplant; his less severely affected mother and sisters were also found to harbor R118C, and his mildly affected brother was found to harbor the TMP1 variant. In addition, Ferreira et al. (2015) reviewed the biochemical and histophathological data on 22 Portuguese and Spanish individuals with R118C and determined this variant does not segregate with a classical Fabry disease phenotype. Current classifications of R118C in ClinVar are also conflicting; it is described as both a likely pathogenic variant and a variant of uncertain significance (SCV000058951.4) by other clinical laboratories. The R118C variant is observed in up to 0.1% of alleles from individuals of European ancestry in large population cohorts, including at least eight individuals who were hemizygous for R118C (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server), indicating that it may be a rare benign variant in this population.Functional studies of the R118C variant have been performed by several investigators (Lukas et al., 2013; Spada et al., 2006; Gaspar et al., 2010). In vitro over-expression studies indicate the variant is abundantly present in cells and is processed correctly but has impaired catalytic activity. Lukas et al. (2013) and Spada et al. (2006) reported R118C shows residual alpha-galactosidase activity ranging from 20% to 29% of wild type. Gaspar et al. (2010) reported that residual alpha-galactosidase activity was 22% of the wild type control mean for one hemizygous male and 60% to 79% of the control mean for two heterozygous females. Thus, alpha-galactosidase activity in individuals carrying this variant appears to be reduced, but does not reach levels typically associated with classic Fabry disease. Spada et al. (2006) reported that R118C has structural characteristics and in vitro over-expression levels similar to other late-onset GLA variants. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
GeneReviews RCV000078277 SCV000494667 uncertain significance Fabry disease 2017-01-05 no assertion criteria provided literature only
Gharavi Laboratory,Columbia University RCV000723556 SCV000920682 likely benign not provided 2018-09-16 no assertion criteria provided research
Illumina Clinical Services Laboratory,Illumina RCV000078277 SCV000916273 likely pathogenic Fabry disease 2018-12-04 criteria provided, single submitter clinical testing Across a selection of the available literature, the GLA c.352C>T (p.Arg118Cys) variant has been identified in at least 15 male probands in a hemizygous state, at least 13 female probands in a heterozygous state, and three females in a homozygous state (two of whom had symptoms consistent with brain involvement and one who was asymptomatic) (Spada et al. 2006; Gaspar et al. 2010; Baptista et al. 2010; Genoni et al.2011; Turaca et al. 2012; Herrera et al. 2014; Caetano et al. 2014; Ferreira et al. 2015). Most probands reported to carry the p.Arg118Cys variant exhibited symptoms of an atypical or late-onset form of Fabry disease, Fabry-related disorders (Fabry-RD), including renal disease, hypertrophic cardiomyopathy or stroke rather than the classic form of Fabry disease. The p.Arg118Cys variant was absent from at least 1040 control chromosomes and is reported at a frequency of 0.00059 in the European American population of the Exome Sequencing Project. The p.Arg118Cys variant results in reduced enzyme activity ranging from 5%-79% of wild type in a variety of proband sample types (Spada et al. 2006; Gaspar et al. 2010; Lukas et al. 2013; Ferreira et al. 2015). The level of enzyme activity found in probands with the p.Arg118Cys variant is too high to be consistent with a diagnosis of classic Fabry disease but is consistent with an atypical presentation. Functional studies of the p.Arg118Cys variant in both HEK293 cells and COS-7 cells demonstrated reduced enzyme activity (between five and 20 percent) compared to the wild type (Spada et al. 2006; Lukas et al. 2013). Based on the collective evidence, the p.Arg118Cys variant is classified as likely pathogenic for an atypical form of Fabry Disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000035303 SCV000917442 uncertain significance not specified 2018-01-24 criteria provided, single submitter clinical testing Variant summary: The GLA c.352C>T (p.Arg118Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in 44/201708 control chromosomes in gnomAD and literature at a frequency of 0.0002181, which does not exceed the estimated maximal expected allele frequency of a pathogenic GLA variant (0.005). The finding of hemizygous occurrences in Gnomad may be evidence against pathogenicity, although the possibility of reduced penetrance and/or subclinical cases cannot be ruled out. This variant has been found in patients predominantly of Portuguese or Spanish ancestry, with clinical features ranging from no symptoms to acute cerebrovascular disease (Rolfs _2013), ischemic stroke, intracerebral hemorrhage, cerebral venous thrombosis (Baptista_2010), kidney diseases (Gaspar_2010, Valbuena_2012, Morais_2008), dilated cardiomyopathy (Golbus_2014), and hypertrophic cardiomyopathy (Caetano_2014). In patients with this variant who presented with cardiological manifestations that are shared by FAB as well as other independent cardiac phenotypes (such as DCM), a deleterious variant was also found (TPM1, D230N; Golbus_2014, LMM unpublished findings). Additionally, this variant has been reported in patients not meeting clinical criteria for FD (Morais_2008, de Greef_2016, Kilarski_2015). Although in vitro studies strongly suggests decreased enzymatic activity associated with this variant (Lukas_2013, Spada_2006), enzymatic evaluation in patients blood or plasma varied from reduced enzymatic level to normal levels. A reputable research group reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the R118C allele and stated that "GLA p.(Arg118Cys) variant does not segregate with FD manifestations at least in a highly-penetrant Mendelian fashion." In addition, clinical laboratories provided conflicting classifications for this variant, from VUS to likely pathogenic. Taken together, this variant is classified as VUS until more definitive data on genotype-phenotype associations and disease progression/natural history and burden become available.
Invitae RCV000078277 SCV000543767 uncertain significance Fabry disease 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 118 of the GLA protein (p.Arg118Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs148158093, ExAC 0.04%, with 8 hemizygous males). This variant has been reported in multiple individuals affected with late-onset Fabry disease (PMID: 16773563, 20110537, 20122163, 21890869, 22551898, 29631605). Due to variable expressivity of the disease, currently there is insufficient data to support disease co-segregation (PMID: 25179549, 25468652). Some studies have called the pathogenicity of this variant into question because it has been observed as homozygous in three related females who do not have Fabry disease, and in individuals who do not have evidence of storage on renal biopsy (PMID: 18830871, 25468652). ClinVar contains an entry for this variant (Variation ID: 42454). Experimental studies have shown that this variant causes partial deficiency with residual alpha-Gal enzyme activity (<25% wild-type activity) in human or mammalian cell lines (PMID: 16773563, 23935525). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035303 SCV000058951 uncertain significance not specified 2018-03-19 criteria provided, single submitter clinical testing The p.Arg118Cys variant in GLA has been reported in 11 individuals with classic or late-onset Fabry disease and segregated with disease in at least 2 affected f amily members. This variant has also been identified in at least 2 individuals w ith reduced a-galactosidase activity, 6 individuals who had stroke, 1 individual who had MI, 1 individual with small fiber neuropathy, 1 individual with juvenil e idiopathic arthritis, 4 individuals with LVH, 1 child with HCM, 2 infants with RCM and DCM, and 3 individuals with other phenotypes (Spada 2006, Gaspar 2010, Baptista 2010, Kiesling 2014, Genoni 2011, Morais 2008, Elliott 2011, Turaca 201 2, Caetano 2014, Pasqualim 2014, Colon 2017, Barajas-Colon 2017, de Greef 2016, Goncalves 2017, Kilarski 2015, Schiffmann 2017, Samuelsson 2014, Ferreira 2015). However, this variant has also been reported in 7 asymptomatic family members, including 3 homozygous females, (Ferreira 2015) and did not segregate with cardi ac phenotypes in 3 affected family members of 2 different families (Golbus 2014, LMM data). This variant has been reported in ClinVar (Variation ID 42454) and h as been identified in 36/90523 of European chromosomes, including 14 hemizygotes , by the Genome Aggregation Database (gnomAD,; dbSNP rs148158093). GLA activity in individuals carrying this variant was reduce d, but did not reach levels associated with classic Fabry disease. Similarly, in vitro functional studies showed enzyme activity of 20-29% (Spada 2006, Lukas 20 13). Computational prediction tools and conservation analysis suggest that the p .Arg118Cys variant may impact the protein, though this information is not predic tive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg118Cys variant is uncertain due to conflicting data. ACMG/AMP Criteria applied: PS4_M; PVS1_Moderate; PP1; PP3; BS4.

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