rs869312141

Variant names:

• chrX-101403908-A-G
• rs869312141
• NM_000169.3:c.272T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-101403908-A-G
• chrX-101403908-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000169.3(GLA):​c.272T>C​(p.Ile91Thr) 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 (★★).

• 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: 9.32

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:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-101403908-A-G is Pathogenic according to our data. Variant chrX-101403908-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 222204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101403908-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.272T>C	p.Ile91Thr	missense_variant	Exon 2 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.272T>C	p.Ile91Thr	missense_variant	Exon 2 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.301-8028A>G		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

May 19, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a significantly reduced enzyme activity compared to wildtype activity (Ishii et al., 2007; Park et al., 2009; Wu et al., 2011; Lukas et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25655062, 27356758, 27560961, 28723748, 29853467, 25382311, 34679477, 27916943, 33714629, 34922431, 9100224, 17555407, 21598360, 23935525, 26415523, Cai2012, Monte2022, Carnicer-Caceres2022, 32023956, 33915609, 19387866, 33922740, 17894781, 20505683, 23430946, 30477121, 30099469, 19287194) -

Fabry disease Pathogenic:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 91 of the GLA protein (p.Ile91Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Fabry disease (PMID: 9100224, 19287194, 23935525, 27560961). ClinVar contains an entry for this variant (Variation ID: 222204). 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: 17555407, 21598360, 26415523). For these reasons, this variant has been classified as Pathogenic. -

GLA-related disorder Pathogenic:1

Jun 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GLA c.272T>C variant is predicted to result in the amino acid substitution p.Ile91Thr. This variant was reported in multiple individuals with Fabry disease (Eng et al. 1997. PubMed ID: 9100224; Ishii et al. 2007. PubMed ID: 17555407; Park et al. 2009. PubMed ID: 19287194; Wu et al. 2011. PubMed ID: 21598360; Lukas et al. 2013. PubMed ID: 23935525; Duro et al. 2018. PubMed ID: 30477121; Pan et al. 2016. PubMed ID: 27560961; Goicoechea et al. 2021. PubMed ID: 33714629). In vitro functional studies show that this variant results in absent or severely reduced alpha-galactosidase A enzymatic activity (Figure 1, Park et al. 2009. PubMed ID: 19287194; Table 1, Wu et al. 2011. PubMed ID: 21598360). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
CardioboostCm	Uncertain	0.90
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.90		Loss of stability (P = 0.0141);.;
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
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: rs869312141; hg19: chrX-100658896;