rs28935486

Positions:

• chrX-101398795-T-A

Variant summary

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

The ENST00000218516.4(GLA):​c.791A>T​(p.Asp264Val) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D264N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA ENST00000218516.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000218516.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398796-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 222393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-101398795-T-A is Pathogenic according to our data. Variant chrX-101398795-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398795-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.791A>T	p.Asp264Val	missense_variant	5/7	ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2	c.300+3338T>A		intron_variant			NP_001186902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.791A>T	p.Asp264Val	missense_variant	5/7	1	NM_000169.3	ENSP00000218516	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2021	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asp264 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 15712228), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant affects GLA protein function (PMID: 21598360). This variant has been observed in individual(s) with Fabry disease (PMID: 7504405, 19387866, 9116979). ClinVar contains an entry for this variant (Variation ID: 10734). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with valine at codon 264 of the GLA protein (p.Asp264Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1993	- -
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	Mar 23, 2021	Variant summary: GLA c.791A>T (p.Asp264Val) 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. The variant was absent in 183472 control chromosomes (gnomAD). c.791A>T has been reported in the literature in at least three unrelated individuals affected with Classic Fabry Disease (example: Eng_1993, Wu_2011, Brown_1997). These data indicate that the variant is likely to be associated with disease. In vitro functional assays show that this variant has no enzymatic activity (example: Wu_2011, Lukas_2013). One other ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. 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)

Sep 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	1.0	D;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	5.0	H;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-8.9	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		1.0
MutPred		0.99		Loss of disorder (P = 0.14);.;
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

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: rs28935486; hg19: chrX-100653783;