Submissions for variant NM_000169.3(GLA):c.644A>G (p.Asn215Ser)

gnomAD frequency: 0.00001  dbSNP: rs28935197

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000157896	SCV000110129	pathogenic	not provided	2018-08-22	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844705	SCV000198194	pathogenic	Fabry disease; Hypertrophic cardiomyopathy	2014-04-02	criteria provided, single submitter	clinical testing	The p.Asn215Ser variant in GLA has been reported in >20 individuals, both male a nd female, with a clinical diagnosis of HCM and/or cardiac Fabry disease, and at least one male with features of classic Fabry disease (Davies 1993, Eng 1994, T opalaglu 1999, Walsh 2017, Oder 2017, LMM unpublished data). This variant has be en identified in 1/80091 of European chromosomes by the Genome Aggregation Datab ase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28935197). Multiple funct ional studies have shown that the p.Asn215Ser variant protein has reduced enzyma tic activity (Mills 2005, Ishii 2007, Wu 2011, Ebrahim 2012, Tian 2013). This va riant has also been reported in ClinVar (Variation ID#10730). In summary, this v ariant meets criteria to be classified as pathogenic for hypertrophic cardiomyop athy based upon presence in probands, very low frequency in controls, and functi onal evidence. ACMG criteria applied: PS3, PM2, PS4
GeneDx	RCV000157896	SCV000207827	pathogenic	not provided	2022-06-02	criteria provided, single submitter	clinical testing	One of the most common later-onset Fabry disease GLA variants reported in individuals of European or North American descent, with cardiac manifestations as the typical presenting feature (Davies et al., 1993; Mills et al., 2005; Spada et al., 2006; Oder et al., 2017; Germain et al., 2018; Sheng et al., 2020); Published functional studies demonstrate a damaging effect as this variant is associated with reduced alpha-galactosidase A enzyme activity compared to wild-type (Spada et al. 2006; Wu et al. 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21972175, 25382311, 28943383, 31020198, 28793143, 15702404, 23568732, 17555407, 23935525, 25611685, 26047621, 27532257, 28728877, 27657681, 28988177, 24582695, 28649509, 31308319, 31956509, 30477121, 31447099, 32150461, 33673806, 32686758, 16773563, 21062768, 15886492, 31393666, 29649853, 29018006, 29621274, 8395937, 32435590, 30023289, 21598360)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000011477	SCV000543776	pathogenic	Fabry disease	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 215 of the GLA protein (p.Asn215Ser). This variant is present in population databases (rs28935197, gnomAD 0.001%). This missense change has been observed in individuals with clinical features of Fabry disease (PMID: 8395937, 11531969, 11914245, 15091117, 15702404, 15712228, 18849176). ClinVar contains an entry for this variant (Variation ID: 10730). 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 not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 16773563, 17555407, 21598360). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000011477	SCV000611200	pathogenic	Fabry disease	2022-04-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618059	SCV000739938	pathogenic	Cardiovascular phenotype	2023-09-29	criteria provided, single submitter	clinical testing	The p.N215S pathogenic mutation (also known as c.644A>G), located in coding exon 5 of the GLA gene, results from an A to G substitution at nucleotide position 644. The asparagine at codon 215 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported in patients with Fabry disease, hypertrophic cardiomyopathy (HCM), and renal disease (Davies JP et al. Hum Mol Genet. 1993;2(7):1051-3; Eng CM et al. Am J Hum Genet. 1993;53(6):1186-97; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Sugarman M et al. Mol Genet Metab Rep, 2018 Jun;15:43-45; Maron MS et al. Am. J. Med., 2018 02;131:200.e1-200.e8; Pasqualim G et al. Clin. Biochem., 2014 May;47:657-62; Militaru S et al. Curr Health Sci J Oct;45:272-277; Sheng B et al. Mol Genet Metab Rep, 2020 Sep;24:100596; Tian ML et al. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2013 Apr;30:185-8; Duro G et al. Int J Mol Sci, 2018 Nov;19; Sakuraba H et al. Mol Genet Metab Rep, 2018 Dec;17:73-79; Koulousios K et al. BMJ Open, 2017 Oct;7:e017098; Varela P et al. Orphanet J Rare Dis, 2020 01;15:30). This variant has also been observed to co-segregate with Fabry disease in multiple families (Tomberli B et al. Eur J Heart Fail. 2013;15(12):1363-73; Maron MS et al. Am. J. Med., 2018 02;131:200.e1-200.e8; Spada M et al. Am J Hum Genet. 2006;79(1):31-40). It has been reported in the heterozygous state in a woman with Fabry disease and progressive cardiac dysfunction, who also had another heterozygous variant in GLA (p.C202R, c.604T>C) (McConnell EJ et al. Eur Heart J Case Rep, 2018 Dec;2:yty122). Individuals with this alteration have been reported to have later age of onset and fewer extracardiac findings when compared to individuals with classic Fabry disease (Thomas A et al. Molec Gen and Metab. 2015 Feb;114(2):S113; Frustaci A et al. Circ Arrhythm Electrophysiol, 2015 Aug;8:799-805; Sugarman M et al. Mol Genet Metab Rep, 2018 Jun;15:43-45; Lavalle L et al. PLoS ONE, 2018 Apr;13:e0193550; Oder D et al. Circ Cardiovasc Genet, 2017 Oct;10; Germain DP et al. Mol Genet Genomic Med, 2018 Apr). In several functional in vitro analyses, this alteration has demonstrated a reduction in alpha-galactosidase A enzyme activity, suggesting variable expressivity among clinical phenotypes depending on residual enzyme activity (Spada M et al. Am J Hum Genet. 2006;79(1):31-40; Wu X et al. Hum. Mutat., 2011 Aug;32:965-77; Ishii S et al. Biochem. J., 2007 Sep;406:285-95; Ebrahim HY et al. J. Inherit. Metab. Dis., 2012 Mar;35:325-34). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011477	SCV000917441	pathogenic	Fabry disease	2019-04-08	criteria provided, single submitter	clinical testing	Variant summary: GLA c.644A>G (p.Asn215Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-06 in 178708 control chromosomes (gnomAD). c.644A>G has been reported in the literature in multiple individuals affected with Fabry Disease. The variant has been identified in numerous patients and families with Fabry disease and is considered a known recurrent mutation that is associated with later-onset disease. A recent multi-center study of 125 Fabry disease patients with this mutation reported their study "confirms that p.N215S is a disease-causing Fabry mutation with severe clinical manifestations essentially limited to the heart until late adulthood, especially in males."(Germain_2018) Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics	RCV000157896	SCV000928264	pathogenic	not provided	2019-03-05	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000011477	SCV001422796	pathogenic	Fabry disease	2020-01-22	criteria provided, single submitter	curation	The p.Asn215Ser variant in GLA has been reported in at least 15 individuals from the literature with Fabry Disease (PMID:21598360, 10666480, 26047621, 23935525, 29621274), segregated with disease in 6 affected relatives from 1 family (PMID: 23818648), and has been identified in 0.001221% (1/81881) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28935197). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as pathogenic by multiple sources including Eurofins Clinical Diagnostics, Ambry Genetics, Fulgent Genetics, GeneDx, Invitae, Laboratory for Molecular Medicine (Partners Healthcare), Mayo Clinic, and OMIM (VariationID:10730). In vitro functional studies provide evidence of decreased enzymatic activity and protein stability, and therefore the p.Asn215Ser variant may impact protein function (PMID: 23935525, 23568732, 21972175, 21598360, 17555407,15702404, 16773563). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual hemizygous for this variant is highly specific for Fabry disease based on the classic phenotype consistent with disease (PMID: 30023289, 29621274,15895718, 7504405, 27532257, 26047621, 23935525, 15702404, 10666480, 7911050, 15091117, 11914245, 11531969, 18849176, 15712228, 21062768, 16773563, 23568732, 8395937). In summary, this variant meets criteria to be classified as pathogenic for Fabry disease based on multiple reports in the literature and ClinVar, reduced enzymatic activity in functional studies, low frequency in the general populaiton, and computational and conservation data. ACMG/AMP Criteria applied: PP4_moderate, PS3_Moderate, PS4, PP3, PP1, PM2_supporting (Richards 2015).
Revvity Omics, Revvity	RCV000157896	SCV002024818	pathogenic	not provided	2023-07-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798000	SCV002042026	pathogenic	Cardiomyopathy	2021-08-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000011477	SCV002054425	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, University of Torino	RCV000011477	SCV002760136	pathogenic	Fabry disease	2022-11-29	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000011477	SCV002768160	pathogenic	Fabry disease	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0103 - Loss of function and dominant negative are known mechanisms of disease in this gene and are associated with Fabry disease (MIM#301500). Loss of function is a known mechanism of disease in males. Females can be affected but with variable severity unexplained by skewed X-inactivation (PMID: 31613176), suggested to be due to the dominant negative mechanism of some variants. Truncating variants in the last exon have been reported with a dominant negative mechanism in females. Gain of function has also been suggested; however more evidence is required (PMIDs: 8878432; 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 asparagine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a condition (0 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated melibiase_2 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a recurrent mutation associated with late-onset Fabry disease (ClinVar, PMIDs: 32435590; 29018006). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Johns Hopkins Genomics, Johns Hopkins University	RCV000011477	SCV004239093	pathogenic	Fabry disease	2023-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000011477	SCV004357520	pathogenic	Fabry disease	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 215 of the GLA protein. Asn215 has been reported as one of the N-linked carbohydrate attachment sites; glycosylation at this site is crucial for the efficient trafficking of the GLA enzyme to the lysosome (PMID: 9620884, 15003450). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that this variant results in reduced GLA enzyme activity when expressed in HEK-293 or COS-7 cells (PMID: 16773563, 17555407, 21598360). This variant has been reported in many individuals affected with Fabry disease, predominantly with cardiac manifestations (left ventricular hypertrophy, arrhythmia) in later adulthood (PMID: 29649853, 32150461, 32435590, 32432376, 32963035, 33335842, 33807900, 35035949, 36087038, 37205992, 37480128, 38002959). This variant has also been reported in individuals affected with classic Fabry disease or renal impairment, but less frequently (PMID: 8395937, 29649853, 32435590, 35035949). It has been shown that this variant segregates with Fabry disease in multiple individuals from two families (PMID: 28943383). This variant has been identified in 1/183422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000157896	SCV004563354	pathogenic	not provided	2023-10-16	criteria provided, single submitter	clinical testing	The GLA c.644A>G; p.Asn215Ser variant (rs28935197) is reported in the literature in numerous individuals and families affected with Fabry disease, typically with later onset and cardiac specific presentation (Eng 1993, Ishii 2007, Lavalle 2018, Oder 2017, Spada 2006, Tomberli 2013). Functional analyses demonstrate that enzyme with this variant has reduced stability/activity (Ishii 2007, Spada 2006). This variant is also reported in ClinVar (Variation ID: 10730). It is only found on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.72). Based on available information, this variant is considered to be pathogenic. References: Eng CM et al. Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease. Am J Hum Genet. 1993 Dec;53(6):1186-97. PMID: 7504405. Ishii S et al. Mutant alpha-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin. Biochem J. 2007 Sep 1;406(2):285-95. PMID: 17555407. Lavalle L et al. Phenotype and biochemical heterogeneity in late onset Fabry disease defined by N215S mutation. PLoS One. 2018 Apr 5;13(4):e0193550. PMID: 29621274. Oder D et al. alpha-Galactosidase A Genotype N215S Induces a Specific Cardiac Variant of Fabry Disease. Circ Cardiovasc Genet. 2017 Oct;10(5):e001691. PMID: 29018006. Spada M et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet. 2006 Jul;79(1):31-40. PMID: 16773563. Tomberli B et al. Coronary microvascular dysfunction is an early feature of cardiac involvement in patients with Anderson-Fabry disease. Eur J Heart Fail. 2013 Dec;15(12):1363-73. PMID: 23818648.
All of Us Research Program, National Institutes of Health	RCV000011477	SCV004821932	pathogenic	Fabry disease	2024-01-06	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 215 of the GLA protein. Asn215 has been reported as one of the N-linked carbohydrate attachment sites and glycosylation at this site is crucial for the efficient trafficking of the GLA enzyme to the lysosome (PMID: 9620884, 15003450). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in reduced GLA enzyme activity when expressed in HEK-293 or COS-7 cells (PMID: 16773563, 17555407, 21598360). This variant has been reported in many individuals affected with Fabry disease, predominantly with cardiac manifestations in late adulthood, especially in males (e.g. left ventricular hypertrophy, arrhythmia) (PMID: 29649853, 32150461, 32435590, 32432376, 32963035, 33335842, 33807900, 35035949, 36087038, etc.). Cases with classic Fabry disease or renal impairment have also been reported but less frequently (e.g. PMID: 8395937, 29649853, 32435590, 35035949). It has been shown that this variant segregates with Fabry disease in multiple individuals from two families (PMID: 28943383). This variant has been identified in 1/183422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000157896	SCV005198395	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing
OMIM	RCV000011477	SCV000031709	pathogenic	Fabry disease	1993-12-01	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000157896	SCV000800936	pathogenic	not provided	2017-02-27	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000157896	SCV000925088	pathogenic	not provided	2016-06-06	no assertion criteria provided	provider interpretation	Given the strong case data and functional studies demonstrating impaired alpha-galactosidase enzyme activity we consider this variant to be disease-causing and we do feel it is suitable for establishing a diagnosis/carrier status of Fabry disease and assessing risk in healthy relatives ("predictive genetic testing"). There is strong case data for this variant, which has been reported in >9 unrelated cases of Fabry disease (not including this patient's family). We have seen the variant in a case of hypertrophic cardiomyopathy. Testing was done at Invitae. The variant has been reported in cases of "variant" phenotypes of Fabry disease, such as cases with isolated cardiac or renal disease, but has also been reported in classic cases. Please note that given the robust case data, the literature review performed in this case was not comprehensive. Eng et al., 1993 from the Desnick group at Mount Sinai reported the Arg215Ser variant in 3 unrelated people with isolated cardiac involvement including left ventricular hypertrophy. Davies et al., 1993 reported the Arg215Ser variant in a patient with classic Fabry disease. Altarescu et al., 2001 reported the Arg215Ser variant in 4 patients from 3 families with signs of Fabry disease, two of whom had angiokeratomas and mucosal anhydrosis (related) and one of whom had a cardiac phenotype (unrelated). All were reported to have alpha-galactosidase A activity of <11% of controls. One compound heterozygous female had a renal phenotype and was noted to have 0.7% alpha-Gal A activity. Sachdev et al., 2002 reported 3 males with the Arg215Ser variant and low alpha-Gal A activity in a study screening men with HCM for Fabry disease. It was not clear whether they may have been related or not or if they had a pure cardiac phenotype or other manifestations. Shabeer et al., 2005 reported the Arg215Ser variant in a female. No specific case data was provided; however, it was noted that the females tested were from Fabry families with unknown variants or clinically suspected to be affected. Erdos et al., 2008 reported the Arg215Ser variant in a Hungarian family with Fabry disease. It was identified in 3 males and 6 females; specific segregation data was not provided. One of the females had severe renal disease with proteinuria diagnosed at 25 and was found to be homozygous for the variant as a result of consanguinity. She and two other family members were noted to not have cardiac involvement. This mutation affects a highly conserved, functional N-glycosylation consensus site of the enzyme, but the expressed enzyme retains some activity. This is consistent with clinical observations of some families with variant presentations confined to one organ system. There is no variation at codon 215 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6/6/2016). The mean coverage at that site in ExAC is 80x with median coverage of 90x and over 95% of individuals with 30x coverage.
Natera, Inc.	RCV000011477	SCV001457723	pathogenic	Fabry disease	2020-09-16	no assertion criteria provided	clinical testing