rs104894835

chrX-101407803-T-C

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.101A>G(p.Asn34Ser) 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. N34D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.75

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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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, 0.984
• PP5: Variant X-101407803-T-C is Pathogenic according to our data. Variant chrX-101407803-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 10724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101407803-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.101A>G	p.Asn34Ser	missense_variant	1/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.301-4133T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.101A>G	p.Asn34Ser	missense_variant	1/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 06, 2022	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 34 of the GLA protein (p.Asn34Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 7504405, 7599642, 10649504). ClinVar contains an entry for this variant (Variation ID: 10724). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GLA function (PMID: 21598360). This variant disrupts the p.Asn34 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 16595074), which suggests that this may be a clinically significant amino acid residue. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 19, 2019	Variant summary: GLA c.101A>G (p.Asn34Ser) results in a conservative amino acid change located in the Glycoside hydrolase, family 27 domain of 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 183447 control chromosomes (gnomAD). c.101A>G has been reported in the literature in multiple individuals affected with Fabry Disease (Eng_1993, Benjamin_2009, Altarescu_2001). The patients were indicated to have less than 10% alpha-Gal activity (Benjamin_2009, Altarescu_2001). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 12, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
CardioboostCm	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0040	D;.
Polyphen		1.0	D;.
Vest4		0.72
MutPred		0.92		Gain of glycosylation at N34 (P = 0.0043);Gain of glycosylation at N34 (P = 0.0043);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs104894835; hg19: chrX-100662791;