Submissions for variant NM_000169.3(GLA):c.427G>A (p.Ala143Thr)

gnomAD frequency: 0.00039  dbSNP: rs104894845

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000224064	SCV000110119	likely pathogenic	not provided	2018-04-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211872	SCV000198197	uncertain significance	not specified	2019-02-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Classified by NVA lite in 2018. 23 papers in HGMD are conflicting. Classifications in clinvar are conflicting: LP (EGL, CHOP), P (Integrated, CMHC), VUS (7 submitters). Gnomad: 0.095% (88 alleles; 26 hemizygotes). 29 hemi males (BF: in gnomad); variant has been associated with mild phenotype
Blueprint Genetics	RCV000157242	SCV000206969	uncertain significance	Cardiomyopathy	2015-08-27	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000011495	SCV000257640	likely pathogenic	Fabry disease	2015-03-06	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224064	SCV000281136	pathogenic	not provided	2015-09-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000011495	SCV000543765	uncertain significance	Fabry disease	2022-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 143 of the GLA protein (p.Ala143Thr). This variant is present in population databases (rs104894845, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with late-onset, mild, or non-classic Fabry disease phenotype with or without Gb-3 storage on cardiac or renal biopsy as well as unaffected adult male relatives (PMID: 9100224, 16773563, 21549080, 22805550, 23219219, 23430526, 23935525, 25040344, 27142856, 28799081). ClinVar contains an entry for this variant (Variation ID: 10748). 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. Experimental studies have shown that this missense change affects GLA function (PMID: 9100224, 21549080, 22805550, 23219219, 23430526, 23935525, 25040344, 27142856). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000211872	SCV000603838	uncertain significance	not specified	2016-09-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211872	SCV000695740	uncertain significance	not specified	2024-05-13	criteria provided, single submitter	clinical testing	Variant summary: GLA c.427G>A (p.Ala143Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 183467 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GLA causing Fabry Disease (0.00055 vs 0.005), allowing no conclusion about variant significance. c.427G>A has been reported in the literature in individuals with a wide spectrum of phenotypes ranging from asymptomatic/normal to mild, late-onset, non-classic Fabry manifestations to classic Fabry disease (examples- Blaydon_2001, Nance_2006, Spada_2006, Monserrat_2007, DeSchoenmakere_2008, Stiles_2020). The variant has also been reported in multiple families in which individuals had Fabry-associated phenotypes such as cardiomyopathy and renal failure, however these findings do not provide conclusive data for co-segregation of the variant with disease (e.g. Spada_2006, deBrabander_2012, Hauth_2018, Valtola_2020). Multiple publications report experimental evidence indicating that the variant results in a reduction of alpha-Gal-A enzyme activity compared to wild-type in both patient cells and cells in which the variant was transiently expressed (e.g. Spada_2006, Lukas_2013, Shabbeer_206, Welford_2018, Lender_2016), however the clinical impact of these findings is not clear, as lyso-Gb-3 levels in some patients with the variant have been reported at levels similar to controls (e.g. Lenders_2016, Lukas_2013, de Brabander_2012, Valtola_2020) and patients have been reported with no typical Gb-3 deposits on kidney biopsy (e.g. Terryn_2012). The following publications have been ascertained in the context of this evaluation (PMID: 18154965, 23935525, 16773563, 9100224, 16533976, 23430526, 18596132, 16595074, 23219219, 11668641, 29867742, 29982630, 27142856, 31949022, 32418857). ClinVar contains an entry for this variant (Variation ID: 10748). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV000618614	SCV000740050	uncertain significance	Cardiovascular phenotype	2023-10-16	criteria provided, single submitter	clinical testing	The p.A143T variant (also known as c.427G>A), located in coding exon 3 of the GLA gene, results from a G to A substitution at nucleotide position 427. The alanine at codon 143 is replaced by threonine, an amino acid with similar properties. This variant was first reported in a newborn with decreased alpha-galactosidase A (α-Gal A ) activity (Eng CM et al. Mol. Med., 1997 Mar;3:174-82). This variant was also reported in a male with a single angiokeratoma and in a female control whose son had a previous diagnosis of Fabry disease (Corry A et al. Dermatol. Online J., 2011 Apr;17:5; Gonzalez-Garay ML et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Oct;110:16957-62) It has been suggested that this is a late-onset variant of Fabry disease and has been identified in individuals with involvement of the heart, cerebrovascular, and renal systems (Dobrovolny R et al. J. Mol. Med., 2005 Aug;83:647-54; Spada M et al. Am. J. Hum. Genet., 2006 Jul;79:31-40; Merta M et al. Nephrol. Dial. Transplant., 2007 Jan;22:179-86; Monserrat L et al. J. Am. Coll. Cardiol., 2007 Dec;50:2399-403; Brouns R et al. Stroke, 2010 May;41:863-8; Terryn W et al. Int. J. Cardiol., 2013 Sep;167:2555-60; Varela P et al. Orphanet J Rare Dis, 2020 01;15:30). However, biopsies of affected organs, including nerve, heart, and kidney, in individuals with this variant have shown no evidence of Fabry disease (Terryn W et al. JIMD Rep., 2013 Jul;8:101-8; Sagnelli A et al. Neuromuscul. Disord., 2014 Mar;24:272-6; Smid BE et al. Clin. Genet., 2015 Aug;88:161-6). Males with normal or residual α-Gal A levels have also been reported (De Brabander I et al. Clin Neurol Neurosurg, 2013 Jul;115:1088-93; Smid BE et al. Clin. Genet., 2015 Aug;88:161-6; Lenders M et al. Orphanet J Rare Dis., 2016 May;11(1):54). In addition, functional studies of this alteration have also shown residual enzyme activity (Shabbeer J et al. Hum. Genomics, 2006 Mar;2:297-309; Lukas J et al. PLoS Genet., 2013 Aug;9(8)e1003632). Based on data from gnomAD, the A allele has an overall frequency of approximately 0.05% (104/205433) total alleles studied, including a total of 29 hemizygotes. The highest observed frequency was 0.23% (44/19165) of Swedish alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000157242	SCV000900936	uncertain significance	Cardiomyopathy	2022-02-03	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845429	SCV000987502	likely pathogenic	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Mendelics	RCV000011495	SCV001141979	uncertain significance	Fabry disease	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224064	SCV001150412	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	GLA: PM5, BS2; RPL36A-HNRNPH2: BS2
University of Iowa Renal Genetics Clinic, University of Iowa	RCV000011495	SCV001250668	likely benign	Fabry disease	2019-07-11	criteria provided, single submitter	clinical testing	The A143T variant has an allele frequency that is greater than expected for Fabry disease and was identified in a 59-year-old male with no evidence of renal disease. Therefore, this variant meets BS1 and BS2 criteria from the ACMG guidelines.
Color Diagnostics, LLC DBA Color Health	RCV000011495	SCV001345836	uncertain significance	Fabry disease	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 143 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant leads to 36% residual alpha-galactosidase A (GLA) enzyme activity in transfected cells (PMID: 16773563). This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 25040344, 32531501, Koraichi et al. 2021, DOI: 10.1016/j.acvdsp.2020.10.086). However, two of them also carried a pathogenic variant in the MYBPC3 gene, which could fully explain the observed phenotype. This variant has been reported in many individuals with Fabry disease-related symptoms, such as renal failure, angiokeratoma, neuropathic pain, stroke, left ventricular hypertrophy, or other cardiac symptoms (PMID: 16773563, 21549080, 23219219, 27142856 , 30902821, 31650418, 31860127, 31907047, 31949022, 32011328, 32281532, 33617311, 35743707). Some adult male relatives carrying this variant have been reported to be asymptomatic (PMID: 21549080, 25040344, 27142856). Male carriers of this variant usually showed high residual GLA enzyme activity, while plasma globotriaosylsphingosine (lyso-Gb3) levels were typically normal. Both enzymatic activity and lyso-Gb3 levels were normal in most female carriers. Furthermore, cardiac and kidney biopsies from four symptomatic carriers showed no buildup of Gb3 in their affected organs (PMID: 23430526, 25040344). One study evaluating outcomes in cases of newborn screening results for this variant showed that plasma globotriaosylsphingosine (lyso-Gb3) levels were normal in all cases evaluated (PMID: 36156392). This variant has been identified in 104/205433 chromosomes (88/92769 Non-Finnish European chromosomes), including 29 hemizygotes, in the general population by the Genome Aggregation Database (gnomAD). This variant allele frequency in the general population is higher than expected for a disease-causing GLA variant. However, due to the observation in many individuals described as having Fabry disease-related phenotypes and some functional studies showing partially reduced GLA enzyme activity, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000011495	SCV001422640	uncertain significance	Fabry disease	2020-01-22	criteria provided, single submitter	curation	The p.Ala143Thr variant in GLA has been reported in the literature in many individuals with non-classic Fabry disease (PMID: 9100224, 22805550, 21549080, 25040344, 23219219, 27142856, 23430526, 23935525), and has been identified in 0.095% (88/92769) of European (non-Finnish) chromosomes, including 26 hemizygous , 0.039% (11/28049) Latino chromosomes, including 2 hemizygotes, 0.016% (3/19041) African chromosomes, including 1 hemizygote, 0.013% (1/7665) Ashkenazi Jewish chromosomes, and 0.0054% (1/18649) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs104894845). This variant has also been reported in ClinVar as likely pathogenic by EGL Genetic Diagnostics, Division of Genomic Diagnostics (The Children's Hospital of Philadelphia), and Integrated Genetics/Laboratory Corporation of America, as a VUS by the Laboratory for Molecular Medicine (Partners Healthcare), Blueprint Genetics, Invitae, ARUP Laboratories, Ambry Genetics, Bioscientia Institut fuer Medizinische Diagnostik GmbH, and GeneReviews, and as Pathogenic by Center for Pediatric Genomic Medicine and OMIM (Variation ID: 10748). In vitro functional studies provide some evidence that the p.Ala143Thr variant may impact protein function (PMID: 21598360, 16595074, 17532296, 16773563, 25040344, 23935525). 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. In summary, the clinical significance of the p.Ala143Thr variant is uncertain. ACMG/AMP Criteria applied: PM5, BS1, PS3_moderate, PP3 (Richards 2015).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000011495	SCV001440522	likely pathogenic	Fabry disease	2022-12-19	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3, PS4_MOD, PM5, PP3
Revvity Omics, Revvity	RCV000224064	SCV002018442	likely pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000011495	SCV002054817	uncertain significance	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000011495	SCV002059450	uncertain significance	Fabry disease	2021-09-15	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000011495	SCV002503838	uncertain significance	Fabry disease	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace alanine with threonine at codon 143 of the GLA protein (p.Ala143Thr). The alanine residue is moderately conserved (100 vertebrates, UCSC), and is located in a predicted disulphide bond that is not present in a known functional domain. There is a small physicochemical difference between alanine and threonine. The variant is present in a large population cohort at a frequency of 0.05% (rs104894845, 104/205,433 alleles, 0 homozygotes, 29 hemizygotes in gnomAD v2.1.1), including 14 hemizygote males with an age range of 30-75 years in the control cohort (BS2). The variant has been identified in individuals varying from unaffected to classical and variant Fabry disease (PMID: 9100224, 23430526). Male hemizygotes typically demonstrate residual alpha galactosidase activity and normal globotriaosylceramide levels in the blood or tissue (PMID: 23430526, 27142856). In vitro expression studies have consistently shown ~35% of wild-type activity for the variant allele, and localisation of the enzyme to the lysosome (PMID: 16595074, 16773563, 23935525). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms - PP3). Additionally, a variant at the same position with a different missense change (p.Ala143Pro) determined to be pathogenic has been seen before (ClinVar ID: 10769 - PM5). The International Fabry Disease Genotype-Phenotype Database (dbFGP) classifies p.Ala143Thr as likely benign, but recommends clinical evaluation of the patient and at-risk family members to determine the clinical relevance of the variant. Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as a VARIANT of UNCERTAIN SIGNIFICANCE. Following criteria are met: BS2, PM5, PP3.
MGZ Medical Genetics Center	RCV000011495	SCV002580644	uncertain significance	Fabry disease	2021-12-21	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000011495	SCV002768639	uncertain significance	Fabry disease	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3C. 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 alanine to threonine. (I) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (75 heterozygotes, 0 homozygotes, 29 hemizygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated alpha galactosidase A domain (PDB, NCBI). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This alternative change (p.Ala143Pro) has been reported multiple times as pathogenic and likely pathogenic, and in patients with classic fabry disease (ClinVar, fabry-database.org). Other alternative changes (p.Ala143Ser, p.Ala143Val) have been reported as VUS (ClinVar, PMID: 31956509). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been described as pathogenic and likely pathogneic, but more recently as likely benign and as a VUS (ClinVar). Fabry disease databases classify this variant as benign and as a polymorphism (dbFGP.org, fabry-database.org). Published literature has reported this variant in patients with fabry disease or cardiomyopathy, and described it as a likely neutral variant, a modifier and as a late-onset variant with incomplete sex- and age- dependant penetrance (PMID: 27142856; PMID: 29867742; PMID: 31949022). (I) 1010 - Functional evidence for this variant is inconclusive. Patients with this variant have been repeatedly reported with decreased but variable, enzyme activity. Residual enzyme activity was not consistently below the diagnostic threshold (PMID: 31949022, PMID: 27142856). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000011495	SCV003807752	uncertain significance	Fabry disease	2022-12-09	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM5 moderated, PP3 supporting, BS2 strong
Department of Human Genetics, Hannover Medical School	RCV000011495	SCV005073982	uncertain significance	Fabry disease	2024-07-09	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000224064	SCV005198396	likely benign	not provided	2023-03-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000224064	SCV005411467	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BS2, PP3
OMIM	RCV000011495	SCV000031727	pathogenic	Fabry disease	2006-03-01	no assertion criteria provided	literature only
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000011495	SCV000484907	uncertain significance	Fabry disease		no assertion criteria provided	clinical testing
GeneReviews	RCV000011495	SCV000494668	not provided	Fabry disease		no assertion provided	literature only
GenomeConnect, ClinGen	RCV000011495	SCV000607180	not provided	Fabry disease		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
GenomeConnect - Invitae Patient Insights Network	RCV000011495	SCV004228517	not provided	Fabry disease		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-04-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004752697	SCV005346410	uncertain significance	GLA-related disorder	2024-07-15	no assertion criteria provided	clinical testing	The GLA c.427G>A variant is predicted to result in the amino acid substitution p.Ala143Thr. This variant occurs relatively frequently in the gnomAD general population database, with a subpopulation allele frequency as high as 0.09% in non-Finnish Europeans and 25 hemizygous individuals documented. However, it has also been identified in a large number of individuals with non-classic Fabry disease, mostly with singular clinical features including stroke (Brouns et al. 2010. PubMed ID: 20360539; Hauth et al. 2018. PubMed ID: 29867742), hypertrophic cardiomyopathy (De Brabander et al. 2013. PubMed ID: 23219219) and a single angiokeratoma (Corry et al. 2011. PubMed ID: 21549080). In many cases, these phenotypes do not segregate in families, including in adult males (Hauth et al. 2018. PubMed ID: 29867742; De Brabander et al. 2013. PubMed ID: 23219219; Lenders et al. 2016. PubMed ID: 27142856). Analysis of alpha-galactosidase A enzyme activity has produced conflicting results, with some studies reporting reduced activity in heterozygous and hemizygous carriers (Eng et al. 1997. PubMed ID: 9100224; Hauth et al. 2018. PubMed ID: 29867742) and others reporting largely normal activity (De Brabander et al. 2013. PubMed ID: 23219219). Gb-3 storage analysis of cardiac or renal biopsy has also yielded conflicting evidence (Terryn et al. 2013. PubMed ID: 23430526; De Brabander et al. 2013. PubMed ID: 23219219; Smid et al. 2015. PubMed ID: 25040344). An alternate nucleotide change affecting the same amino acid (p.Ala143Pro), has been reported to be pathogenic for Fabry disease (Human Gene Mutation Database). In ClinVar, the c.427G>A variant has conflicting interpretations ranging from likely benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/10748/). We suspect that this variant may contribute to Fabry disease phenotypes with incomplete penetrance; however, at this time, we classify it as a variant of uncertain significance given the conflicting genetic and functional data.