rs28935196
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000169.3(GLA):c.484T>C(p.Trp162Arg) 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. W162L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000169.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLA | NM_000169.3 | c.484T>C | p.Trp162Arg | missense_variant | 3/7 | ENST00000218516.4 | |
RPL36A-HNRNPH2 | NM_001199973.2 | c.300+6238A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLA | ENST00000218516.4 | c.484T>C | p.Trp162Arg | missense_variant | 3/7 | 1 | NM_000169.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
Fabry disease Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1993 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 28, 2018 | 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. Experimental studies have shown that this missense change results in a GLA protein with no alpha-galactosidase A enzyme activity (PMID: 21598360). This variant has been reported as hemizygous in individuals affected with Fabry disease (PMID: 15100373, 12778775, 7504405). ClinVar contains an entry for this variant (Variation ID: 10728). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 162 of the GLA protein (p.Trp162Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 30, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at