NM_000169.3:c.525C>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000169.3(GLA):c.525C>G(p.Asp175Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000984 in 1,208,879 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 40 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.00011 ( 0 hom. 39 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 1.23

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 made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant X-101401654-G-C is Benign according to our data. Variant chrX-101401654-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 573833.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000108 (118/1097136) while in subpopulation NFE AF= 0.000138 (116/841121). AF 95% confidence interval is 0.000117. There are 0 homozygotes in gnomad4_exome. There are 39 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome4 at 39 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.525C>G	p.Asp175Glu	missense_variant	Exon 3 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.525C>G	p.Asp175Glu	missense_variant	Exon 3 of 7	1	NM_000169.3	ENSP00000218516.4		P06280
RPL36A-HNRNPH2	ENST00000409170.3 link	c.300+6197G>C		intron_variant	Intron 4 of 4	4		ENSP00000386655.4		H7BZ11

Frequencies

GnomAD3 genomes

AF:

0.00000895

AC:

AN:

111743

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33921

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000327

AC:

AN:

183473

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

67909

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000610

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000108

AC:

118

AN:

1097136

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

362502

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000138

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000895

AC:

AN:

111743

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

33921

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fabry disease

Uncertain:3Benign:1

Mar 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glutamic acid at codon 175 of the GLA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant causes partial reduction of GLA enzyme activity (PMID: 23935525, 31036492). However, clinical relevance of this observation is not known. This variant has been reported in two unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32531501). This variant has also been identified in 6/183473 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 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 175 of the GLA protein (p.Asp175Glu). This variant is present in population databases (rs782722844, gnomAD 0.006%). This missense change has been observed in individual(s) with Fabry disease and/or hypertrophic cardiomyopathy (PMID: 27532257, 32531501; internal data). ClinVar contains an entry for this variant (Variation ID: 573833). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 31036492). 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. -

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:1

May 17, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27657681, 27532257, 23935525) -

GLA-related disorder

Uncertain:1

May 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GLA c.525C>G variant is predicted to result in the amino acid substitution p.Asp175Glu. This variant was reported in a patients with Fabry disease and related cardiac phenotypes (Lukas et al. 2013. PubMed ID: 23935525; Patient 5 in Patel et al. 2015. PubMed ID: 25655062; Azevedo et al. 2020. PubMed ID: 32531501). In one case, a patient was noted to also have variants in other HCM gene (Azevedo et al. 2020. PubMed ID: 32531501; Patient 101 in Supplementary Table 2, Mademont-Soler et al. 2017. PubMed ID: 28771489). Functional analysis of this variant showed that enzymatic activity was mildly impacted and ~90% compared to wildtype (Lukas et al. 2013. PubMed ID: 23935525). This variant is reported in 0.0061% of alleles in individuals of European, including five hemizygous individuals (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-100656642-G-C) which is likely too frequent to be associated with high penetrance. In ClinVar, this variant has conflicting interpretations regarding its pathogenicity ranging from likely benign to uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/573833/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Jun 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D175E variant (also known as c.525C>G), located in coding exon 3 of the GLA gene, results from a C to G substitution at nucleotide position 525. The aspartic acid at codon 175 is replaced by glutamic acid, an amino acid with highly similar properties. This variant has been detected in multiple individuals with hypertrophic cardiomyopathy (HCM), some of whom have variants in other cardiac genes (Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465; Walsh R et al. Genet. Med., 2017 02;19:192-203; Azevedo O et al. Am. Heart J., 2020 08;226:114-126). This variant was also identified in a male individual with Anderson-Fabry disease who had sudden cardiac death (Patel V et al. Heart, 2015 Jun). Based on data from gnomAD, the G allele has an overall frequency of 0.003% (6/183473) total alleles studied, with 5 hemizygotes observed. The highest observed frequency was 0.02208% (1/4530) of Other alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

CardioboostCm

Benign

0.020

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.77

D;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.33

T;T

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

1.5

L;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.4

N;.

REVEL

Uncertain

0.42

Sift

Benign

0.30

T;.

Sift4G

Benign

0.27

T;.

Polyphen

0.058

B;.

Vest4

0.15

MutPred

0.49

Loss of loop (P = 0.2237);.;

MVP

0.88

MPC

0.68

ClinPred

0.029

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.40

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.35

Position offset: 5

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over