X-101401752-C-T
Variant names:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BS1_SupportingBS2
The NM_000169.3(GLA):c.427G>A(p.Ala143Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000581 in 1,208,710 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 200 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00037 ( 0 hom., 9 hem., cov: 23)
Exomes 𝑓: 0.00060 ( 0 hom. 191 hem. )
Consequence
GLA
NM_000169.3 missense
NM_000169.3 missense
Scores
8
8
2
Clinical Significance
Conservation
PhyloP100: 6.12
Genes affected
GLA (HGNC:4296): (galactosidase alpha) This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]
RPL36A-HNRNPH2 (HGNC:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM1
In a disulfide_bond (size 30) in uniprot entity AGAL_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000169.3
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000374 (42/112236) while in subpopulation NFE AF= 0.000638 (34/53302). AF 95% confidence interval is 0.000468. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Hemizygotes in GnomAd4 at 9 Mitochondrial gene
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000374 AC: 42AN: 112182Hom.: 0 Cov.: 23 AF XY: 0.000262 AC XY: 9AN XY: 34336
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GnomAD3 exomes AF: 0.000545 AC: 100AN: 183467Hom.: 0 AF XY: 0.000412 AC XY: 28AN XY: 67907
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GnomAD4 genome 0.000374 AC: 42AN: 112236Hom.: 0 Cov.: 23 AF XY: 0.000262 AC XY: 9AN XY: 34400
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:7Uncertain:20Benign:3Other:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Fabry disease Pathogenic:3Uncertain:12Benign:1Other:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | 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 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 19, 2022 | _x000D_ Criteria applied: PS3, PS4_MOD, PM5, PP3 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 02, 2025 | 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 13, 2023 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Dec 21, 2021 | - - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | 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. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2006 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Mar 06, 2015 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Department of Human Genetics, Hannover Medical School | Jul 09, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | - | - - |
| Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | 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). - |
| Likely benign, criteria provided, single submitter | clinical testing | University of Iowa Renal Genetics Clinic, University of Iowa | Jul 11, 2019 | 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. - |
| not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Sep 15, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Mar 30, 2023 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Dec 09, 2022 | ACMG classification criteria: PM5 moderated, PP3 supporting, BS2 strong - |
not provided Pathogenic:3Uncertain:2Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 05, 2024 | The GLA c.427G>A; p.Ala143Thr variant (rs104894845; ClinVar ID: 10748) is reported in the literature in individuals with features of Fabry disease but also in unaffected individuals (De Brabander 2013, Hauth 2018, Hemelsoet 2021, Lenders 2016, Smid 2015, Terryn 2013, Valtola 2020). Affected individuals with this variant are often reported with late-onset, mild, or otherwise atypical clinical features of Fabry disease, and while residual enzyme activity is often reduced in patients, carriers often show normal levels of lyso-G3b (De Brabander 2013, Hauth 2018, Hemelsoet 2021, Lenders 2016, Lukas 2013, Smid 2015, Terryn 2013, Valtola 2020). This variant is found in the general population with an overall allele frequency of 0.05% (104/205,433 alleles, including 29 hemizygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.858). Although evidence suggests this variant is unlikely to cause classic Fabry disease, a potential role in late-onset or atypical disease cannot be ruled out. Thus, due to limited and conflicting information, the clinical significance of this variant is uncertain at this time. References: De Brabander I et al. Phenotypical characterization of a-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young. Clin Neurol Neurosurg. 2013 Jul;115(7):1088-93. PMID: 23219219. Hauth L et al. Galactosidase Alpha p.A143T Variant Fabry Disease May Result in a Phenotype With Multifocal Microvascular Cerebral Involvement at a Young Age. Front Neurol. 2018 May 16;9:336. PMID: 29867742. Hemelsoet D et al. Screening for Fabry Disease in Male Patients With Arrhythmia Requiring a Pacemaker or an Implantable Cardioverter-Defibrillator. Circulation. 2021 Feb 23;143(8):872-874. PMID: 33617311. Lenders M et al. Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant. Orphanet J Rare Dis. 2016 May 4;11(1):54. PMID: 27142856. Lukas J et al. Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in fabry disease. PLoS Genet. 2013;9(8):e1003632. PMID: 23935525 Smid BE et al. Diagnostic dilemmas in Fabry disease: a case series study on GLA mutations of unknown clinical significance. Clin Genet. 2015 Aug;88(2):161-6. PMID: 25040344. Terryn W et al. Questioning the Pathogenic Role of the GLA p.Ala143Thr "Mutation" in Fabry Disease: Implications for Screening Studies and ERT. JIMD Rep. 2013;8:101-8. PMID: 23430526 Valtola K et al. Cardiomyopathy associated with the Ala143Thr variant of the alpha-galactosidase A gene. Heart. 2020 Apr;106(8):609-615. PMID: 31949022. - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2024 | GLA: PM5, BS2; RPL36A-HNRNPH2: BS2 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 10, 2018 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 01, 2024 | BS2, PP3 - |
| Likely benign, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Mar 30, 2023 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 27, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 14, 2015 | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 14, 2025 | 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 estimated 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, 38618884). ClinVar contains an entry for this variant (Variation ID: 10748). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 08, 2019 | 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 - |
Cardiomyopathy Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 27, 2015 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 03, 2022 | - - |
Primary familial hypertrophic cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
GLA-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 15, 2024 | 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. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 21, 2024 | 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
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