X-101407902-A-G

Position:

• chrX-101407902-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000169.3(GLA):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-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 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.51

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 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101407902-A-G is Pathogenic according to our data. Variant chrX-101407902-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 495694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101407902-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.2T>C	p.Met1?	start_lost	1/7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.2T>C	p.Met1?	start_lost	1/7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.301-4034A>G		intron_variant		4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fabry disease Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2016	Variant summary: The GLA c.2T>C (p.Met1Thr) variant involves the alteration of a non-conserved nucleotide and results disruption of the START codon of GLA. 4/5 in silico tools predict a damaging outcome for this substitution. This variant is absent in 87229 control chromosomes while it was reported in at least two patients with Fabry disease indicating causality. GLA activity measured in a male patient showed the variant to result in ~14% activity of that of the wild type protein further supporting a pathogenic impact. Moreover, variants impacting the same codon are listed in HGMD as disease causing (M1R, M1I, M1L, M1K, M1V ) indicating the Met1 residue to be a mutational hotspot and its clinical importance. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 01, 2018	This variant is expected to result in an absent or disrupted protein product. If translation initiation is rescued by the downstream methionine at codon 42, this would result in loss of the signal peptide cleavage site (PMID: 8807334). For these reasons, this variant has been classified as Pathogenic. This variant has been reported in several individuals affected with Fabry disease (PMID: 9100224, 28672034, 28275245).  Other nucleotide substitutions affecting the initiator codon (c.2T>G and c.3G>A) have also been reported in individuals with Fabry disease (PMID: 12175777, 8807334). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the GLA mRNA. The next in-frame methionine is located at codon 42. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 04, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 18, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.20	T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.6	D
PROVEAN	Benign	-0.26	N;.
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.15	B;.
Vest4		0.86
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0236);Gain of catalytic residue at M1 (P = 0.0236);
MVP		1.0
ClinPred		0.89	D
GERP RS		4.0
Varity_R		0.88
gMVP		0.96

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: rs1555987232; hg19: chrX-100662890;