rs28935490

chrX-101398432-C-AchrX-101398432-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

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. 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
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications U:4 B:20 O:2
• Conservation: PhyloP100: 0.136

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 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: {Benign=8, Likely_benign=12, Uncertain_significance=3, 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. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 104 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.937G>T	p.Asp313Tyr	missense_variant	6/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+2975C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.937G>T	p.Asp313Tyr	missense_variant	6/7	1	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

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

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

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

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:4 Benign:20 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Uncertain:3 Benign:6 Other:1

Likely benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Mar 11, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeMIA	-	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. -
other, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2018	- pseudodeficiency allele
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This 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. -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Jul 23, 2020	- -

not provided Uncertain:1 Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 29, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 10, 2023	- -
other, criteria provided, single submitter	clinical testing	Eurofins 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).
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	The 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) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	GLA: BP2, BP5, BS3:Supporting, BS1 -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 02, 2012	p.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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 13, 2023	Variant 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 submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 29, 2016	- -

Hypertrophic cardiomyopathy Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Sep 29, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Sudden unexplained death Benign:1

Likely benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 27, 2015

The 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 submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 19, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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

Other links and lift over

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