rs28935486
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000169.3(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 (★★).
Frequency
Genomes: not found (cov: 23)
Consequence
GLA
NM_000169.3 missense
NM_000169.3 missense
Scores
14
3
1
Clinical Significance
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: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, 0.995
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 |
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 | ENSP00000218516.4 | ||
RPL36A-HNRNPH2 | ENST00000409170.3 | c.300+3338T>A | intron_variant | 4 | ENSP00000386655.4 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1993 | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;.
Polyphen
D;.
Vest4
MutPred
Loss of disorder (P = 0.14);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at