rs869312324

chrX-101401632-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000169.3(GLA):c.547G>A(p.Gly183Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G183D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.85

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 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101400757-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 562419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-101401632-C-T is Pathogenic according to our data. Variant chrX-101401632-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 222281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101401632-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.547G>A	p.Gly183Ser	missense_variant, splice_region_variant	3/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+6175C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.547G>A	p.Gly183Ser	missense_variant, splice_region_variant	3/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 01, 2020	Variant summary: GLA c.547G>A (p.Gly183Ser) 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 183417 control chromosomes (gnomAD). c.547G>A has been reported in the literature in multiple individuals affected with Fabry Disease (example: Shabbeer_2002, Tuttolomondo_2017, Sayer_2008, Benjamin_2009, Duro_2018, Jain_2018). Few of these patients were presented with a classic phenotype. These data indicate that the variant is very likely to be associated with disease. The variant resulted in very low enzymatic activity both in patients and in in vitro cell based assays (example: Shabbeer_2002, Wu_2011, Tuttolomondo_2017, Sayer_2008, Benjamin_2009). One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. In the HGMD database, there are several other variants affecting the same codon and nearby codons (example: p.G183A , p.G183R , p.G183D , p.G183V, p.Y184N, p.L180V ) suggesting this area might be mutational hotspot. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 28, 2017

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2022

The p.G183S pathogenic mutation (also known as c.547G>A), located in coding exon 3 of the GLA gene, results from a G to A substitution at nucleotide position 547. The glycine at codon 183 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 3, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in unrelated males reported to have features consistent with Fabry disease (FD) including reduced enzyme activity, and females with this variant have also been reported to have some features of FD (Shabbeer J et al. Mol Genet Metab, 2002 May;76:23-30; Sayer JA et al. Kidney Int, 2008 Nov;74:1366; Benjamin ER et al. J Inherit Metab Dis, 2009 Jun;32:424-40; McCloskey S et al. F1000Res, 2018 Mar;7:356; Tuttolomondo A et al. Oncotarget, 2017 Sep;8:61415-61424; Jain R et al. JACC Cardiovasc Imaging, 2018 Apr;11:644-647; Moiseev S et al. Nephron, 2019 Jan;141:249-255). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). These nucleotide and amino acid positions are highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.72
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.7	D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0080	D;.
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.89		Gain of disorder (P = 0.0454);.;
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.93
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869312324; hg19: chrX-100656620;