ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.427G>A (p.Ala143Thr) (rs104894845)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000224064 SCV000110119 likely pathogenic not provided 2018-04-10 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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
Invitae RCV000011495 SCV000543765 uncertain significance Fabry disease 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 143 of the GLA protein (p.Ala143Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs104894845, ExAC 0.1%, with 18 hemizygous males). This variant has been reported in many individuals described to have a late-onset, mild, or non-classic Fabry disease phenotype (PMID: 9100224, 22805550, 21549080, 25040344, 23219219, 27142856, 23430526, 23935525) and in an individual with a more severe phenotype (PMID: 29867742). In addition, this variant has been seen to co-occur in some relatives with symptoms that may be consistent with late-onset Fabry disease such as cardiomyopathy and renal failure but at this time segregation remains inconclusive (PMID: 21549080, 16773563, 23219219). Recent studies have called the pathogenicity of this variant into question because some adult male relatives with this variant have been asymptomatic (PMID: 21549080, 27142856, 28799081) and symptomatic individuals with this variant typically do not have evidence of Gb-3 storage on cardiac or renal biopsy (PMID: 25040344, 23219219, 23430526). However, one female patient with this variant has been reported with Gb-3 deposits on cardiac biopsy (PMID: 22805550). ClinVar contains an entry for this variant (Variation ID: 10748). Biochemical studies have shown that patients with this missense change have reduced alpha-galactosidase activity, but typically with some level of residual enzyme activity. Plasma Gb-3 and lyso Gb-3 levels are typically normal (PMID: 9100224, 22805550, 21549080, 25040344, 23219219, 27142856, 23430526, 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.
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 2021-04-22 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). 16 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=1; uncertain signifiance, n=11; pathogenic/likely pathogenic, n=4). Based on the evidence outlined above, until additional information becomes available, the variant was classified as uncertain significance.
Ambry Genetics RCV000618614 SCV000740050 uncertain significance Cardiovascular phenotype 2020-08-06 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 newborn with decreased alpha galactosidase A (<span style="font-family:dejavusans">&alpha;-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 <span style="font-family:dejavusans">&alpha;-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 0.22% (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 2017-08-02 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 Praxis fuer Humangenetik Tuebingen RCV000224064 SCV001150412 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
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 Health, Inc RCV000011495 SCV001345836 uncertain significance Fabry disease 2020-10-12 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 143 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). 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 two individuals affected with hypertrophic cardiomyopathy (PMID: 25040344, 32531501). However, both 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). 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). This variant is fairly common in the general population and has been identified in 104/205433 chromosomes (88/92769 Non-Finnish European chromosomes) by the Genome Aggregation Database (gnomAD). In summary, this variant has been seen in many patients described as having Fabry disease-related phenotypes, but has also been observed in many asymptomatic individuals. Based on the available evidence, this variant is classified as a Variant of Uncertain Significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV000011495 SCV001440522 pathogenic Fabry disease 2019-01-01 criteria provided, single submitter clinical testing
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 uncertain significance Fabry disease 2017-01-05 no assertion criteria 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.
Broad Institute Rare Disease Group, Broad Institute RCV000011495 SCV001422640 uncertain significance Fabry disease 2020-01-22 no assertion criteria provided 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).

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