X-101401752-C-T

Position:

• chrX-101401752-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM5 BS2

The ENST00000218516.4(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A143P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00060 (0 hom. 191 hem.)
• Consequence: GLA ENST00000218516.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:20 B:3 O:3
• 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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in ENST00000218516.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101401752-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 9 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.427G>A	p.Ala143Thr	missense_variant	3/7	ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2	c.300+6295C>T		intron_variant			NP_001186902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.427G>A	p.Ala143Thr	missense_variant	3/7	1	NM_000169.3	ENSP00000218516	P1

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 42 AN: 112182 Hom.: 0 Cov.: 23 AF XY: 0.000262 AC XY: 9 AN XY: 34336

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000638

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000545 AC: 100 AN: 183467 Hom.: 0 AF XY: 0.000412 AC XY: 28 AN XY: 67907

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000401

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000602 AC: 660 AN: 1096474 Hom.: 0 Cov.: 29 AF XY: 0.000528 AC XY: 191 AN XY: 361882

Gnomad4 AFR exome AF: 0.000265

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000173

Gnomad4 NFE exome AF: 0.000730

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000374 AC: 42 AN: 112236 Hom.: 0 Cov.: 23 AF XY: 0.000262 AC XY: 9 AN XY: 34400

Gnomad4 AFR AF: 0.000162

Gnomad4 AMR AF: 0.000189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000165

Gnomad4 NFE AF: 0.000638

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000877 Hom.: 37

Bravo AF: 0.000412

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00134 AC: 9

ExAC AF: 0.000717 AC: 87

EpiCase AF: 0.000927

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:20 Benign:3 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Pathogenic:3 Uncertain:12 Benign:1 Other:3

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. -
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	Centogene AG - the Rare Disease Company	Sep 15, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 -
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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 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	- -
Uncertain significance, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2022	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. -
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	MGZ Medical Genetics Center	Dec 21, 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. -
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. -
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	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:3 Uncertain:1 Benign:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 27, 2023	- -
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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 01, 2024	BS2, PP3 -

not specified Uncertain:3

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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 13, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2016	- -

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

Oct 16, 2023

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
CardioboostCm	Uncertain	0.63
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.61
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.015	D;.
Polyphen		1.0	D;.
Vest4		0.84
MVP		1.0
MPC		1.3
ClinPred		0.19	T
GERP RS		5.1
Varity_R		0.76
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894845; hg19: chrX-100656740; COSMIC: COSV54508001; COSMIC: COSV54508001;