X-101397903-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 3P and 7B. PM1PP2BP4_ModerateBS1_SupportingBS2

The NM_000169.3(GLA):c.1196G>C(p.Trp399Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,205,957 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000034 ( 0 hom. 18 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:15O:1

Conservation

PhyloP100: 3.44

Publications

8 publications found

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]

GLA links:

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]

RPL36A-HNRNPH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000169.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 218 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.8759 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Fabry disease.

BP4

Computational evidence support a benign effect (MetaRNN=0.11818567).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000443 (5/112782) while in subpopulation SAS AF = 0.00181 (5/2767). AF 95% confidence interval is 0.000712. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 18 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.1196G>C	p.Trp399Ser	missense_variant	Exon 7 of 7	ENST00000218516.4	NP_000160.1	P06280Q53Y83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4 link	c.1196G>C	p.Trp399Ser	missense_variant	Exon 7 of 7	1	NM_000169.3	ENSP00000218516.4		P06280
RPL36A-HNRNPH2	ENST00000409170.3 link	c.300+2446C>G		intron_variant	Intron 4 of 4	4		ENSP00000386655.4		H7BZ11

Frequencies

GnomAD3 genomes

AF:

0.0000444

AC:

AN:

112729

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00180

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000818

AC:

AN:

183471

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000338

AC:

AN:

1093175

Hom.:

Cov.:

AF XY:

0.0000502

AC XY:

AN XY:

358725

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26315

American (AMR)

AF:

0.00

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19359

East Asian (EAS)

AF:

0.00

AC:

AN:

30194

South Asian (SAS)

AF:

0.000611

AC:

AN:

54035

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4124

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

837493

Other (OTH)

AF:

0.0000871

AC:

AN:

45920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000443

AC:

AN:

112782

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34962

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31112

American (AMR)

AF:

0.00

AC:

AN:

10687

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3607

South Asian (SAS)

AF:

0.00181

AC:

AN:

2767

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6202

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53311

Other (OTH)

AF:

0.00

AC:

AN:

1540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fabry disease

Pathogenic:1Uncertain:8

Oct 23, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jan 27, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces tryptophan with serine at codon 399 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 53% residual alpha-galactosidase A (GLA) enzyme activity in transfected cells (PMID: 26415523). This variant has been reported in four individuals affected with Fabry disease (PMID: 26415523, 28253518, 29794742). This variant has also been identified in 15/183471 chromosomes (15/19080 South Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). 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. -

Jan 17, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 399 of the GLA protein (p.Trp399Ser). This variant is present in population databases (rs782449839, gnomAD 0.08%). This missense change has been observed in individual(s) with late-onset Fabry disease (PMID: 26415523, 28253518, 33495303). ClinVar contains an entry for this variant (Variation ID: 217414). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Trp399Ser variant in GLA has been reported in at least 3 individuals with Fabry disease (PMID: 26415523,28253518, 29794742), and has been identified in 0.08% (15/19080) of South Asian chromosomes, including 7 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs782449839). This variant has also been reported in ClinVar as likely pathogenic by Albrecht-Kossel-Institute (Medical University Rostock) and a VUS by Invitae (ID: 217414). In vitro functional studies provide some evidence that the p.Trp399Se variant may not impact protein function (PMID: 26415523). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of individuals hemizygous for this variant is highly specific for Fabry disease based on the classical phenotype which is consistent with disease (PMID: 26415523, 28253518, 28728877). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS1, PP4, PS4_supporting, BS3_supporting (Richards 2015). -

Nov 30, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 02, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Uncertain:4

Nov 01, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:provider interpretation

p.Trp399Ser (c.1196G>C) in GLA, Exon 7, (NM_000169.2; chrX-100652891-C-G) SCICD Classification: variant of uncertain significance, probably benign based on the allele frequency. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Case data (not including our patient): Reported with Fabry. Per the lab report "This variant has been reported in individuals affected with late-onset Fabry disease (PMID: 26415523,)." Population data: Highest MAF in South Asian population: 0.07835% in gnomAD exomes (ExAC) -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:1

Oct 22, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GLA c.1196G>C (p.Trp399Ser) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-05 in 183471 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GLA causing Fabry Disease (8.2e-05 vs 0.005), allowing no conclusion about variant significance. c.1196G>C has been reported in the literature in individuals affected with Later-onset Fabry Disease and slightly elevated levels of lyso-Gb3 and in one homozygous female with particularly severe clinical manifestations including cardiomyopathy and beginning kidney failure (Nowak_2017, Nowak_2018, Oder_2018). The later-onset male patient cohort has also been subsequently cited by others. These report(s) do not provide unequivocal conclusions about association of the variant with classic Fabry Disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50% of normal alpha-Galactosidase A enzyme activity in-vitro (example, Lukas_2016). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

See cases

Uncertain:1

Jan 20, 2022

Institute of Human Genetics, University Hospital Muenster

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PM1,PM2,PP3 -

Hypertrophic cardiomyopathy 1

Uncertain:1

May 18, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Migalastat response

Other:1

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

- Pharmacological Chaperone response: no

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

CardioboostCm

Benign

0.049

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Uncertain

0.57

D;.

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.63

T;T

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.12

T;T

MetaSVM

Pathogenic

1.3

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

3.4

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.070

N;.

REVEL

Uncertain

0.55

Sift

Benign

0.54

T;.

Sift4G

Benign

0.82

T;.

Polyphen

0.57

P;.

Vest4

0.71

MutPred

0.56

Gain of disorder (P = 5e-04);.;

MVP

0.93

MPC

1.2

ClinPred

0.12

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.94

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over