Submissions for variant NM_000169.3(GLA):c.352C>T (p.Arg118Cys)

gnomAD frequency: 0.00040  dbSNP: rs148158093

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035303	SCV000058951	uncertain significance	not specified	2019-02-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. 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 family members. This variant has also been identified in at least 2 individuals with reduced a-galactosidase activity, 6 individuals who had stroke, 1 individual who had MI, 1 individual with small fiber neuropathy, 1 individual with juvenile 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 2012, 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 cardiac 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 has been identified in 36/90523 of European chromosomes, including 14 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148158093). GLA activity in individuals carrying this variant was reduced, but did not reach levels associated with classic Fabry disease. Similarly, in vitro functional studies showed enzyme activity of 20-29% (Spada 2006, Lukas 2013). Computational prediction tools and conservation analysis suggest that the p.Arg118Cys variant may impact the protein, though this information is not predictive 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.
GeneDx	RCV000723556	SCV000207820	likely benign	not provided	2023-05-23	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000078277	SCV000543767	uncertain significance	Fabry disease	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 118 of the GLA protein (p.Arg118Cys). This variant is present in population databases (rs148158093, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with mild, atypical or late-onset Fabry disease (PMID: 16773563, 18830871, 20110537, 20122163, 21890869, 22551898, 25179549, 25468652, 29631605, 30569317, 30773290). ClinVar contains an entry for this variant (Variation ID: 42454). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLA protein function. Experimental studies have shown that this missense change affects GLA function (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.
Ambry Genetics	RCV000619869	SCV000736028	uncertain significance	Cardiovascular phenotype	2022-06-29	criteria provided, single submitter	clinical testing	The c.352C>T (p.R118C) alteration is located in exon 2 (coding exon 2) of the GLA gene. This alteration results from a C to T substitution at nucleotide position 352, causing the arginine (R) at amino acid position 118 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769541	SCV000900937	uncertain significance	Cardiomyopathy	2019-08-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000078277	SCV000904642	uncertain significance	Fabry disease	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 118 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant causes partially reduced GLA enzyme activity in mammalian cells (PMID: 23935525, 16773563). This variant has been reported in individuals affected with late-onset Fabry disease (PMID: 20122163, 22551898, 25468652, 35743707) and with hypertrophic cardiomyopathy (PMID: 31291414, 32531501, Koraichi et al. 2021, DOI: 10.1016/j.acvdsp.2020.10.086). 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). This variant has been observed in an individual affected with idiopathic end-stage renal failure (PMID: 31566927). His three sons and two daughters who carried this variant were asymptomatic with normal GLA enzyme activity. This variant has been identified in 48/205229 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and includes 17 hemizygous observations. In summary, while this variant has been reported in individuals affected with GLA-related disorders, the role of this variant in disease cannot be determined conclusively due to the frequent variant observation in unaffected individuals. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035303	SCV000917442	uncertain significance	not specified	2023-09-05	criteria provided, single submitter	clinical testing	Variant summary: GLA c.352C>T (p.Arg118Cys) results in a non-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 0.00023 in 184752 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GLA causing Fabry Disease (0.00023 vs 0.005). However, the finding of 17 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, ischemic stroke, intracerebral hemorrhage, cerebral venous thrombosis, kidney diseases, dilated cardiomyopathy, and hypertrophic cardiomyopathy (e.g. Morais_2008, Baptista_2010, Gaspar_2010, Valbuena_2012, Rolfs _2013, Caetano_2014, Golbus_2014, Alharbi_2019, Varela_2020, Delarosa-Rodriguez_2021). In patients (harboring this variant) who presented with cardiological manifestations that are shared by Fabry disease (FD) as well as other independent cardiac phenotypes (such as DCM), a deleterious variant was also found (TPM1 D230N; Golbus_2014). Additionally, this variant has been reported in patients who did not meet clinical criteria for FD (e.g. Morais_2008, Kilarski_2015, de Greef_2016, Nowak_2019, Azevedo_2020, Stiles_2020). Furthermore, Ferreira et al (2015) reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the R118C allele and concluded that the variant did not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease. Additionally, co-occurrence of the variant in cis with a pathogenic variant (GLA deletion of exons 3 and 4) was reported in a multi-generational family affected with Fabry Disease, providing supporting evidence for a benign role (Barbeito-Caamano_2018). Although in vitro studies strongly suggest 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. Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority of submitters classified the variant as VUS (n=17), and others classified it as either likely pathogenic (n=2) or likely benign (n=2). 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.
Blueprint Genetics	RCV000723556	SCV000927454	uncertain significance	not provided	2017-10-26	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000769541	SCV000995284	uncertain significance	Cardiomyopathy	2019-01-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000078277	SCV001141981	uncertain significance	Fabry disease	2019-05-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000078277	SCV001367920	uncertain significance	Fabry disease	2019-05-09	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3,PP5,BP6. This variant was detected in hemizygous state.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000078277	SCV001422636	uncertain significance	Fabry disease	2020-01-22	criteria provided, single submitter	curation	The p.Arg118Cys variant in GLA has been reported in at least 11 individuals with Fabry disease (PMID: 28596458, 16773563, 20122163, 21890869, 22551898, 28299312, 28409012, 21946453, 20110537, 25468652, 24582695, 24661928, 18830871), and has been identified in 0.044% (41/92573) of European (non-Finnish) chromosomes, including 16 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148158093). This variant has also been reported in ClinVar as a VUS by the Laboratory for Molecular Medicine, GeneDx, Invitae, Ambry Genetics, GeneReviews, and the University of Washington Medical Center and as likely pathogenic by EGL Genetic Diagnostics (Variation ID: 42454). In vitro functional studies provide some evidence that the p.Arg118Cys variant may impact protein function (PMID: 23935525, 28646478, 16773563, 25468652, 20122163). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classical phenotype consistent with the disease (PMID: 28596458, 16773563, 20122163, 21890869, 22551898, 28299312, 28409012, 21946453, 20110537, 25468652, 24582695, 24661928, 18830871). This variant was found in cis with another pathogenic variant, suggesting that it may not cause disease (PMID: 28941980) In summary, the clinical significance of the p.Arg118Cys variant is uncertain due to conflicting data. ACMG/AMP Criteria applied: BS1, PS3_moderate, PP4, BP2 (Richards 2015).
Mayo Clinic Laboratories, Mayo Clinic	RCV000723556	SCV001713146	uncertain significance	not provided	2022-11-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000078277	SCV002054820	uncertain significance	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000078277	SCV002580615	uncertain significance	Fabry disease	2022-01-18	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000078277	SCV002767180	uncertain significance	Fabry disease	2022-03-31	criteria provided, single submitter	clinical testing	Curated 19/3/2021: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS - 3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Fabry disease (MIM#301500). Truncating variants in the last exon have been reported with a dominant negative mechanism, while those predicted to undergo nonsense mediated decay been reported with a loss of function mechanism. Missense variants have been reported with both aforementioned mechanisms. Gain of function has also been suggested, however more evidence is required (PMID: 8878432; PMID: 31613176). (I) 0109 - This gene is associated with X-linked disease. Both males and females have been reported with Fabry disease, though the latter are more rarely reported and tend to have milder disease (OMIM, PMID: 31613176). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (30 heterozygotes, 1 homozygote, 13 hemizygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (4 heterozygotes, 0 homozygotes, 1 hemizygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated melibiase 2 domain (Pfam). (I) 0701 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg118His) has previously been reported as a VUS in at least one publication (PMID 30477121). Alternative amino acid changes to serine, glycine, proline and leucine have not been reported in patients, however, were studied via site-directed mutagenesis and found to result in enzymatic activities ranging from 40-70% of wild-type, which is higher that 20% found for p.(Arg118Cys) (PMID: 23935525). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as a variant of uncertain significance (11x) and likely pathogenic (2x) in ClinVar. In the literature, it has been reported in both male and female patients, where the variant results in residual enzyme activities that is consistent with mild, late onset Fabry disease (PMID: 16773563; 20122163; 30569317; 31291414). However, the pathogenicity of this variant has been called into question by at least one publication by demonstrating that the variant does not segregate with Fabry disease (PMID: 25468652) and in another publication where a different variant in GLA was deemed to be causative of FD the family (PMID:28941980). Lukas et al (2013) refer to this variant's clinical phenotype as being a "variant phenotype" (PMID: 23935525). The "variant phenotype" is explained by Andrade et al (2008) as having a low level of residual alpha-galactosidase activity that protects patients from developing classic FD, however some patients may present with late onset end-organ failure (PMID: 18003767). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Gaspar et al (2010) measured alpha-galactose activity in patient leukocytes and found that the variant conferred a reduction of enzyme activity to 35% of wild-type in 1 hemizygous male and 60%-79% of wild-type in 2 heterozygous females (PMID: 20122163). In vitro functional studies of this variant showed a reduction of enzymatic actiivities ranging between 20-29% in 2 independent studies (PMID: 1677356; 23935525). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV000723556	SCV003816857	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000723556	SCV004033323	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	GLA: BS2
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000723556	SCV005198398	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000723556	SCV000110117	likely pathogenic	not provided	2018-01-11	flagged submission	clinical testing
GeneReviews	RCV000078277	SCV000494667	not provided	Fabry disease		no assertion provided	literature only
CSER _CC_NCGL, University of Washington	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.
Gharavi Laboratory, Columbia University	RCV000723556	SCV000920682	likely benign	not provided	2018-09-16	no assertion criteria provided	research
Natera, Inc.	RCV000078277	SCV001458760	uncertain significance	Fabry disease	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004752731	SCV005361393	uncertain significance	GLA-related disorder	2024-06-10	no assertion criteria provided	clinical testing	The GLA c.352C>T variant is predicted to result in the amino acid substitution p.Arg118Cys. This variant has an extensive history of conflicting literature regarding it's contribution to Fabry disease phenotypes. It has been reported in multiple individuals with late-onset Fabry disease (examples include: Spada et al. 2006. PubMed ID: 16773563; Baptista et al. 2010. PubMed ID: 20110537; Gaspar et al. 2010. PubMed ID: 20122163). However, it was also shown not to segregate with clinical, biochemical or histopathology features of Fabry disease in a large cohort, including in three phenotypically unaffected individuals who were homozygous for the c.352C>T variant (Ferreira et al. 2015. PubMed ID: 25468652). This variant has been observed in 48 of ~205,000 alleles in the gnomAD general population database including 17 hemizygous males. Enzyme analysis from patient cell lines and transient mammalian expression systems indicate that the p.Arg118Cys substitution causes a reduction in activity (<25% of wild-type; Lukas et al. 2013. PubMed ID: 23935525; Spada et al. 2006. PubMed ID: 16773563). In ClinVar, this variant has conflicting interpretations including uncertain and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/42454/). An internal summary of amino acid substitution prediction programs finds conflicting predictions for the p.Arg118Cys change (Liu et al. 2016. PMID: 26555599). Taken together, it is possible that the c.352C>T allele poses an increased risk for Fabry-associated phenotypes; however, at present, this variant is classified as a variant of uncertain significance for Mendelian disease.