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rs28935490

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000169.3(GLA):c.937G>T(p.Asp313Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,207,947 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,531 hemizygotes in GnomAD Genomes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D313N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., 104 hem., cov: 23)
Exomes 𝑓: 0.0038 ( 9 hom. 1427 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

4
8
5

Clinical Significance

Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications U:4B:20O:2

Conservation

PhyloP100: 0.136
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000169.3
BP4
Computational evidence support a benign effect (MetaRNN=0.021395475).
BP6
Variant X-101398432-C-A is Benign according to our data. Variant chrX-101398432-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity, other]. Clinvar id is 10738.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=12, Uncertain_significance=3, Benign=8, other=2}. Variant chrX-101398432-C-A is described in Lovd as [Benign]. Variant chrX-101398432-C-A is described in Lovd as [Likely_pathogenic]. Variant chrX-101398432-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00314 (350/111368) while in subpopulation NFE AF= 0.00528 (280/53077). AF 95% confidence interval is 0.00477. There are 1 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd at 104 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GLANM_000169.3 linkuse as main transcriptc.937G>T p.Asp313Tyr missense_variant 6/7 ENST00000218516.4
RPL36A-HNRNPH2NM_001199973.2 linkuse as main transcriptc.300+2975C>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GLAENST00000218516.4 linkuse as main transcriptc.937G>T p.Asp313Tyr missense_variant 6/71 NM_000169.3 P1

Frequencies

GnomAD3 genomes
AF:
0.00314
AC:
350
AN:
111314
Hom.:
1
Cov.:
23
AF XY:
0.00310
AC XY:
104
AN XY:
33516
show subpopulations
Gnomad AFR
AF:
0.000719
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00153
Gnomad ASJ
AF:
0.00643
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00230
Gnomad FIN
AF:
0.000505
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00527
Gnomad OTH
AF:
0.00401
GnomAD3 exomes
AF:
0.00303
AC:
556
AN:
183499
Hom.:
2
AF XY:
0.00352
AC XY:
239
AN XY:
67935
show subpopulations
Gnomad AFR exome
AF:
0.000760
Gnomad AMR exome
AF:
0.00201
Gnomad ASJ exome
AF:
0.00681
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00252
Gnomad FIN exome
AF:
0.000625
Gnomad NFE exome
AF:
0.00443
Gnomad OTH exome
AF:
0.00419
GnomAD4 exome
AF:
0.00384
AC:
4215
AN:
1096579
Hom.:
9
Cov.:
30
AF XY:
0.00394
AC XY:
1427
AN XY:
361981
show subpopulations
Gnomad4 AFR exome
AF:
0.000455
Gnomad4 AMR exome
AF:
0.00205
Gnomad4 ASJ exome
AF:
0.00624
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00327
Gnomad4 FIN exome
AF:
0.000790
Gnomad4 NFE exome
AF:
0.00432
Gnomad4 OTH exome
AF:
0.00328
GnomAD4 genome
AF:
0.00314
AC:
350
AN:
111368
Hom.:
1
Cov.:
23
AF XY:
0.00310
AC XY:
104
AN XY:
33580
show subpopulations
Gnomad4 AFR
AF:
0.000717
Gnomad4 AMR
AF:
0.00153
Gnomad4 ASJ
AF:
0.00643
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00230
Gnomad4 FIN
AF:
0.000505
Gnomad4 NFE
AF:
0.00528
Gnomad4 OTH
AF:
0.00396
Alfa
AF:
0.00467
Hom.:
212
Bravo
AF:
0.00285
TwinsUK
AF:
0.00243
AC:
9
ALSPAC
AF:
0.00554
AC:
16
ESP6500AA
AF:
0.000522
AC:
2
ESP6500EA
AF:
0.00431
AC:
29
ExAC
AF:
0.00333
AC:
404
EpiCase
AF:
0.00469
EpiControl
AF:
0.00504

ClinVar

Significance: Conflicting classifications of pathogenicity; other
Submissions summary: Uncertain:4Benign:20Other:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Fabry disease Uncertain:3Benign:6Other:1
Uncertain significance, no assertion criteria providedliterature onlyOMIMJan 01, 2013- -
Likely benign, criteria provided, single submitterresearchCSER _CC_NCGL, University of WashingtonMar 11, 2015- -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 16, 2018- -
other, criteria provided, single submitterclinical testingInvitaeDec 27, 2018- pseudodeficiency allele
Likely benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, criteria provided, single submitterclinical testingAl Jalila Children's Genomics Center, Al Jalila Childrens Speciality HospitalJul 23, 2020- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitterclinical testingCeMIA-The c.937G>T (p.Asp313Tyr) variant, located in exon 6 of the GLA gene, has been previously reported to be associated with Fabry disease (PMID: 20122163, 23393592, 26993117, 7504405), however this variant does not lead to severe organ manifestations as seen in genotypes known to be causal for classical FD (PMID: 27059467). Functional studies support that the variant renders the protein unstable at neutral pH resulting in a pseudodeficiency in plasma, but the enzyme was stable at lysosomal pH, which prompts further investigation to detect a second, causative mutation (PMID: 14635108). The variant was identified in seventeen individuals (7 hemizygous males, 10 heterozygous females), in which only thirteen (6 hemizygous males, 7 heterozygous females) were affected with Fabry disease. The presentation of the disease in the patients indicates that the mutation results in a milder phenotype, with later onset of symptoms. Bioinformatic analysis by SIFT and PolyPhen2 algorithms predicted this mutation as deleterious and probably damaging, respectively. It has been detected in 0.304% alleles worldwide (gnomAD database) and its allele frequency is higher than that expected for Fabry disease. Taking all the above into account and according to ACMG Guidelines (Criteria: PM1, PP2, PP3, BS1, BP5) the variant has contradictory interpretation of pathogenicity, therefore is considered as variant of uncertain significance. -
Benign, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabMay 18, 2021- -
not provided Uncertain:1Benign:4Other:1
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2023GLA: BP2, BP5, BS3:Supporting, BS1 -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 10, 2023- -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJun 29, 2017- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 03, 2023- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015The D313Y variant listed below is associated with pseudodeficiency for alpha-galactosidase A activity. D313Y reduces the in vitro activity of the alpha-galactosidase A enzyme to approximately 60-70% of normal. The presence of the D313Y variant does not cause Fabry disease [Froissart et al. (2003) Mol. Genet. Metab. 80 (3):307-14 (PMID: 14680977); Niemann et al. (2013) JIMD Rep 7 :99-102 (PMID: 23430502)].; This variant is associated with the following publications: (PMID: 32246457, 32109691, 32281532, 30477121, 31860127, 31291414, 30830284, 29227985, 28703315, 28988177, 29037082, 28299312, 28276057, 27600940, 29044343, 25382311, 27153395, 26993117, 7504405, 20110537, 23393592, 23935525, 18057066, 14680977, 23430502, 22773828, 18297328, 14635108, 24356988, 22537551, 23219219, 25078086, 21896204, 20122163, 16773563) -
other, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 22, 2018- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
not specified Benign:4
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 13, 2023Variant summary: GLA c.937G>T (p.Asp313Tyr) 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 0.003 in 207410 control chromosomes (in the gnomAD database and publication data), including 3 homozygotes and 266 hemizygotes. This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in GLA causing Fabry Disease (0.003 vs 0.005), allowing no clear conclusions about variant significance, though the presence of high numbers of hemizygotes suggests a generally benign role for the variant. In the literature, this variant has been observed in large phenotypic range of patients, from clinically normal to classic Fabry disease patients, including patients with cardiac-, renal and cerebrovascular manifestations. However, in multiple cases co-occurrences with other (potentially) pathogenic variants have been reported, providing supporting evidence for a benign role. Specifically, this variant was found in three male patients with Classical Fabry disease together (i.e. in cis) with other pathogenic missense variants G411D, R112C and C172G; and these latter mutations, but not D313Y, individually showed impaired enzyme activity and were presumably misfolded and/or unstable, resulting in their retention in the endoplasmic reticulum and subsequent proteosome degradation (Guffon_1998, Yasuda_2003). Moreover, in one of the reported families this variant did not co-segregate with disease, did not result in reduced alpha-Gal-A activity or clinical Fabry manifestations in carrier males, neither did the presence of this variant in carrier Fabry females enhance the phenotype of the known causative mutation in the GLA gene (G271S) in this study (Hasholt_2017). In addition, the variant of interest was also found in a female patient (phase is unknown) together with a pathogenic variant c.835C>G (p.Q279E) in an internal LCA sample. Functional studies have shown that D313Y does not disrupt enzyme structure, has >90% residual enzyme activity and is stable at lysosomal pH (4.5), but has ~60% residual enzyme activity at pH 7.4 as it is unstable at this pH, resulting in a pseudodeficiency when measured from plasma (Yasuda_2003). Overall, functional studies suggest that the D313Y variant is a functional polymorphism rather than a disease-causing variant. Several studies reported the variant to be associated with a risk of neurologic involvement, particularly late-onset cerebrovascular disease, white matter lesions and small fiber neuropathy (e.g. Brouns_2010, Lenders_2010, Effraimidis_2020, Von Cossel_2021). In summary, based on the evidence outlined above, though the D313Y variant might be associated with a risk for late-onset neurologic manifestations, it does not cause Fabry disease. The following publications have been ascertained in the context of this evaluation (PMID: 25078086, 20110537, 29044343, 11668641, 20360539, 23219219, 32246457, 7504405, 14680977, 20122163, 9452111, 29037082, 28988177, 23393592, 26415523, 23430502, 29530533, 24829596, 29631605, 33543778, 14635108, 27832731, 32109691, 28276057, 35971858). Eighteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=17) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteJul 29, 2016- -
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 02, 2012p.Asp313Tyr in exon 6 of GLA: This variant is not expected to have clinical sign ificance for cardiomyopathy since it has been identified in 0.4% (29/6728) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/; dbSNP rs28935490). It has been rep orted in patients with clinical manifestations ranging from classic Fabry diseas e to isolated HCM (Eng 1993, Blaydon 2001, Sachdev 2002, Froissart 2003, Yasuda 2003, Morita 2006, Monserrat 2007) and while cell culture studies showed that th e mutant GLA protein retains ~60% of the normal activity, the p.Asp313Tyr varian t renders the protein unstable at neutral pH resulting in a pseudodeficiency in plasma (Yasuda 2003). In males with classic Fabry disease, it usually occurs wit h a second GLA variant (Eng 1993, Yasuda 2003), and is highly likely insufficien t to cause classic Fabry disease in isolation. -
Hypertrophic cardiomyopathy Benign:3
Benign, criteria provided, single submitterclinical testingCohesion PhenomicsSep 29, 2022- -
Likely benign, criteria provided, single submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoJul 26, 2017- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Sudden unexplained death Benign:1
Likely benign, criteria provided, single submitterresearchAgnes Ginges Centre for Molecular Cardiology, Centenary InstituteMar 27, 2015The GLA Asp313Tyr variant has been previously reported to be associated with Fabry disease and observed in isolated HCM cases, however this variant is often identified in combination with another variant which is able to explain the disease phenotype (Eng et al., 1993; Sachdev B et al., 2002; Yasuda M et al., 2003; Monserrat L et al., 2007). The population frequency in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) is 0.003 alleles (275/87762); and the frequency in the European (non-Finnish) sub-population is 0.004 (211/48000). We have identified this variant in a 16 yo boy who had a sudden cardiac arrest with no pre-morbid diagnosis and Greek ethnicity. Post-mortem examination was unremarkable and there is no family history of any cardiac disease. Based on the frequency of the GLA Asp313Tyr variant in 0.4% of the population, we do not expect this variant to cause disease in isolation. We therefore classify this variant as "likely benign". -
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioApr 19, 2023- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 11, 2018This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Uncertain
0.070
Cadd
Benign
16
Dann
Uncertain
0.98
DEOGEN2
Pathogenic
0.98
D;.
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Benign
0.021
T;T
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.5
M;.
MutationTaster
Benign
0.76
D
PrimateAI
Benign
0.34
T
PROVEAN
Uncertain
-3.2
D;.
REVEL
Uncertain
0.61
Sift
Uncertain
0.0010
D;.
Sift4G
Pathogenic
0.0010
D;.
Polyphen
1.0
D;.
Vest4
0.24
MVP
0.99
MPC
1.9
ClinPred
0.025
T
GERP RS
-5.0
Varity_R
0.86
gMVP
0.99

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28935490; hg19: chrX-100653420; COSMIC: COSV54510729; COSMIC: COSV54510729; API