rs782722844

chrX-101401654-G-CchrX-101401654-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP6 BS2

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). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 1.23

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 Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000169.3
• 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: {Uncertain_significance=5, Likely_benign=2}.
• BS2: High Hemizygotes in GnomAdExome at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.525C>G	p.Asp175Glu	missense_variant	3/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+6197G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.525C>G	p.Asp175Glu	missense_variant	3/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000895 AC: 1 AN: 111743 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33921

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: 6 AN: 183473 Hom.: 0 AF XY: 0.0000736 AC XY: 5 AN XY: 67909

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.: 0 Cov.: 29 AF XY: 0.000108 AC XY: 39 AN XY: 362502

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: 1 AN: 111743 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33921

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: 1

ALSPAC AF: 0.00 AC: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 01, 2023	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 26, 2022	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 and/or hypertrophic cardiomyopathy (PMID: 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 573833). 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 does not substantially affect GLA function (PMID: 23935525). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2019	This variant is associated with the following publications: (PMID: 27657681, 27532257, 23935525) -

GLA-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2020

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	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	18
Dann	Uncertain	0.97
DEOGEN2	Uncertain	0.77	D;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T;T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.83	N
PrimateAI	Benign	0.39	T
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	T
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

Other links and lift over

dbSNP: rs782722844; hg19: chrX-100656642;