rs869312432

chrX-101398543-T-C

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.826A>G(p.Ser276Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S276R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.02

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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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-101398541-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 524215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-101398543-T-C is Pathogenic according to our data. Variant chrX-101398543-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 222427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398543-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.826A>G	p.Ser276Gly	missense_variant	6/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+3086T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.826A>G	p.Ser276Gly	missense_variant	6/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 14, 2019	This sequence change replaces serine with glycine at codon 276 of the GLA protein (p.Ser276Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Fabry disease (PMID: 21598360, 26415523). Experimental studies have shown that this missense change results in loss of alpha-galactosidase enzyme activity (PMID: 21598360, 19387866, 26415523). Two different missense substitutions at this codon (p.Ser276Arg, p.Ser276Asn) have been reported in individuals affected with Fabry disease (PMID: 15776423, Invitae). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 16, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.80
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.94		Gain of relative solvent accessibility (P = 0.1571);.;
MVP		1.0
MPC		1.7
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs869312432; hg19: chrX-100653531;