rs727503949
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000169.3(GLA):c.658C>T(p.Arg220*) variant causes a stop gained change. 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000169.3 stop_gained
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000169.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GLA | NM_000169.3 | MANE Select | c.658C>T | p.Arg220* | stop_gained | Exon 5 of 7 | NP_000160.1 | ||
| GLA | NM_001406747.1 | c.781C>T | p.Arg261* | stop_gained | Exon 6 of 8 | NP_001393676.1 | |||
| GLA | NM_001406748.1 | c.658C>T | p.Arg220* | stop_gained | Exon 5 of 6 | NP_001393677.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GLA | ENST00000218516.4 | TSL:1 MANE Select | c.658C>T | p.Arg220* | stop_gained | Exon 5 of 7 | ENSP00000218516.4 | ||
| RPL36A-HNRNPH2 | ENST00000409170.3 | TSL:4 | c.300+3471G>A | intron | N/A | ENSP00000386655.4 | |||
| GLA | ENST00000649178.1 | c.781C>T | p.Arg261* | stop_gained | Exon 6 of 8 | ENSP00000498186.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 30
GnomAD4 genome
ClinVar
Submissions by phenotype
Fabry disease Pathogenic:6
Variant summary: GLA c.658C>T (p.Arg220X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Arg227X, p.Lys240fsX9, p.Ile242fsX8). The variant was absent in 178788 control chromosomes. c.658C>T has been reported in the literature in multiple individuals affected with Fabry Disease (Germain_2002, Meaney_1994, Mills_2005, Ries_2005, Schafer_2005, Shin_2007) and is reported to be non-enhanceable by 1-deoxygalactonojirimycin (DGJ) (Shin_2007). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GLA p.Arg220Ter (c.658C>T) is a nonsense variant that introduces a premature stop codon at amino acid position 220, creating a truncated protein that is predicted to undergo nonsense-mediated mRNA decay. This variant has been observed in at least one proband affected with Fabry disease (PMID:7951217;23980562;30468909;33036343;17206462;38002959;27676143;39182239;36873653;19346951). The variant was found to segregate with disease in at least one affected family (PMID:7951217;23980562;30468909;33036343;17206462;38002959;27676143;39182239). A de novo occurrence of this variant has been observed in at least one affected individual (PMID:36873653). At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:26415523). It is absent or not present at a significant frequency in gnomAD. In conclusion, we classify GLA p.Arg220Ter (c.658C>T) as a pathogenic variant.
This sequence change creates a premature translational stop signal (p.Arg220*) in the GLA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Fabry disease (PMID: 7951217, 15702404, 23980562). ClinVar contains an entry for this variant (Variation ID: 167140). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction); Variant is absent from gnomAD (v2, v3 and v4); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. It has also been reported in at least two individuals with classic Fabry disease (PMID: 39609713); Other NMD-predicted variant(s) comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). Additional information: This variant is heterozygous; This gene is associated with X-linked disease. Both males and females have been reported with Fabry disease; however, females are more rarely reported and tend to have milder disease (OMIM, PMID: 31613176); Loss of function and dominant negative are known mechanisms of disease in this gene and are associated with Fabry disease (MIM#301500). Loss of function is a known mechanism of disease in males. Females can be affected but with variable severity unexplained by skewed X-inactivation (PMID: 31613176), suggested to be due to the dominant negative mechanism of some variants. Truncating variants in the last exon have been reported with a dominant negative mechanism in females. Gain of function has also been suggested; however, more evidence is required (PMID: 8878432, 31613176).
not provided Pathogenic:4
Cardiovascular phenotype Pathogenic:1
The p.R220* pathogenic mutation (also known as c.658C>T), located in coding exon 5 of the GLA gene, results from a C to T substitution at nucleotide position 658. This changes the amino acid from an arginine to a stop codon within coding exon 5. This variant was reported in individual(s) with features consistent with Fabry disease (Meaney C et al. Hum Mol Genet, 1994 Jun;3:1019-20; Mills K et al. J Inherit Metab Dis, 2005;28:35-48; Shin SH et al. Biochem Biophys Res Commun, 2007 Jul;359:168-73; Duro G et al. Int J Mol Sci, 2018 Nov;19; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445; Nampoothiri S et al. JIMD Rep, 2020 Nov;56:82-94; Yoshida S et al. Orphanet J Rare Dis, 2020 Aug;15:220; Ambry internal data). In an assay testing GLA function, this variant showed a functionally abnormal result (Shin SH et al. Biochem Biophys Res Commun, 2007 Jul;359:168-73). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at