rs730880450

Positions:

• chrX-101398873-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000169.3(GLA):​c.713G>A​(p.Ser238Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S238G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.12

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant X-101398873-C-T is Pathogenic according to our data. Variant chrX-101398873-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398873-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.713G>A	p.Ser238Asn	missense_variant	5/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+3416C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.713G>A	p.Ser238Asn	missense_variant	5/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2012	The Ser238Asn mutation in the GLA gene has been reported in two unrelated males with late onset HCM and low plasma galactosidase A activity (Monserrat L et al., 2007). Mutations in nearby residues (Trp236Arg, Trp236Cys, Trp236Leu, Ile239Thr, Ile242Thr) have been reported in association with Fabry disease, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Ser238Asn was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The variant is found in HCM panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2015	- -

Fabry disease Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2020	Variant summary: GLA c.713G>A (p.Ser238Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183483 control chromosomes. c.713G>A has been reported in the literature in individuals with phenotypes ranging from classic Fabry disease (Vieitez_2018) to seemingly isolated GLA-HCM (Monserrat_2007), to late-onset Fabry disease, which may be related to skewed X-inactivation with predominant expression of the wild-type GLA allele (Echevarria_2015). In vitro enzyme activity was shown to be 36% of wild-type (Lukas_2013). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 25, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 238 of the GLA protein (p.Ser238Asn). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GLA function (PMID: 23935525). 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. ClinVar contains an entry for this variant (Variation ID: 180841). This missense change has been observed in individual(s) with Fabry disease (PMID: 18154965). It has also been observed to segregate with disease in related individuals. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2020

The p.S238N variant (also known as c.713G>A), located in coding exon 5 of the GLA gene, results from a G to A substitution at nucleotide position 713. The serine at codon 238 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in Fabry disease and hypertrophic cardiomyopathy cohorts, and appeared to segregate with disease in one family (Monserrat L et al. J Am Coll Cardiol, 2007 Dec;50:2399-403; Echevarria L et al. Clin Genet, 2016 Jan;89:44-54; Jain R et al. JACC Cardiovasc Imaging, 2018 Apr;11:644-647; Vieitez I et al. Orphanet J Rare Dis, 2018 04;13:52; Viswanathan SK et al. PLoS One, 2017 Nov;12:e0187948). In vitro functional studies showed this variant with approximately 37% of wild-type alpha-galactosidase A activity (Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632; Nowak A et al. J Inherit Metab Dis, 2020 03;43:326-333). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
CardioboostCm	Uncertain	0.82
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.021	D;.
Sift4G	Benign	0.063	T;.
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.89		Loss of helix (P = 0.0167);.;
MVP		0.98
MPC		1.7
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs730880450; hg19: chrX-100653861;