rs730880451

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000169.3(GLA):​c.801G>A​(p.Met267Ile) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 23)

Consequence

GLA
NM_000169.3 missense, splice_region

Scores

11
6
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.91
Variant links:
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]

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ACMG classification

Classification made for transcript

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, 0.984
PP5
Variant X-101398785-C-T is Pathogenic according to our data. Variant chrX-101398785-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 180842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398785-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GLANM_000169.3 linkuse as main transcriptc.801G>A p.Met267Ile missense_variant, splice_region_variant 5/7 ENST00000218516.4 NP_000160.1 P06280Q53Y83

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GLAENST00000218516.4 linkuse as main transcriptc.801G>A p.Met267Ile missense_variant, splice_region_variant 5/71 NM_000169.3 ENSP00000218516.4 P06280
RPL36A-HNRNPH2ENST00000409170.3 linkuse as main transcriptc.300+3328C>T intron_variant 4 ENSP00000386655.4 H7BZ11

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Fabry disease Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 15, 2019This variant has been reported in several individuals affected with Fabry disease (PMID: 10666480, 11668641, Invitae). ClinVar contains an entry for this variant (Variation ID: 180842). For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this missense change has a moderate effect on GLA protein aggregation but results in a reduction of GLA enzymatic activity in vitro (PMID: 22773828). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 267 of the GLA protein (p.Met267Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant also falls at the last nucleotide of exon 5 of the GLA coding sequence, which is part of the consensus splice site for this exon. -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 18, 2014The M267I mutation in the GLA gene has been reported in a single patient with Fabry disease who was hemizygous for the mutation and had a plasma alpha-Gal A activity of 0.2U/ml (Topaloglu A et al., 1999). Other mutations affecting the same residue (M267R, M267T) as well as mutations in neighboring residues (D266V, D266E, L268S) have been reported in association with Fabry disease, further supporting the functional importance of this residue and this region of the protein. Furthermore, the M267I mutation was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, M267I in the GLA gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 21, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
CardioboostCm
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.72
D
BayesDel_noAF
Pathogenic
0.80
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;.
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
3.6
H;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-3.8
D;.
REVEL
Pathogenic
0.97
Sift
Uncertain
0.0020
D;.
Sift4G
Uncertain
0.0020
D;.
Polyphen
1.0
D;.
Vest4
0.98
MutPred
0.89
Gain of sheet (P = 0.1451);.;
MVP
0.99
MPC
1.8
ClinPred
1.0
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.32
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.32
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs730880451; hg19: chrX-100653773; API