NM_000169.3:c.1088G>A
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 13P and 5B. PM1PM5PP2PP5_Very_StrongBS1_SupportingBS2
The NM_000169.3(GLA):c.1088G>A(p.Arg363His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,207,965 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. 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. R363C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000169.3 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 8 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.1088G>A | p.Arg363His | missense | Exon 7 of 7 | NP_000160.1 | ||
| GLA | NM_001406747.1 | c.1211G>A | p.Arg404His | missense | Exon 8 of 8 | NP_001393676.1 | |||
| GLA | NR_164783.1 | n.1167G>A | non_coding_transcript_exon | Exon 8 of 8 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GLA | ENST00000218516.4 | TSL:1 MANE Select | c.1088G>A | p.Arg363His | missense | Exon 7 of 7 | ENSP00000218516.4 | ||
| RPL36A-HNRNPH2 | ENST00000409170.3 | TSL:4 | c.300+2554C>T | intron | N/A | ENSP00000386655.4 | |||
| GLA | ENST00000649178.1 | c.1211G>A | p.Arg404His | missense | Exon 8 of 8 | ENSP00000498186.1 |
Frequencies
GnomAD3 genomes 0.000125 AC: 14AN: 111964Hom.: 0 Cov.: 23 show subpopulations
GnomAD2 exomes AF: 0.0000545 AC: 10AN: 183364 AF XY: 0.0000885 show subpopulations
GnomAD4 exome AF: 0.0000155 AC: 17AN: 1096001Hom.: 0 Cov.: 30 AF XY: 0.0000249 AC XY: 9AN XY: 361377 show subpopulations
Age Distribution
GnomAD4 genome 0.000125 AC: 14AN: 111964Hom.: 0 Cov.: 23 AF XY: 0.000264 AC XY: 9AN XY: 34152 show subpopulations
ClinVar
Submissions by phenotype
Fabry disease Pathogenic:13Uncertain:1
GLA c.1088G>A is a missense variant that changes the amino acid at residue 363 from Arginine to Histidine. This variant has been observed in at least one proband affected with Fabry disease (PMID:11668641;20716442;33204599;31392112;33022387;33437642;26937405;28360401). Functional studies have been reported; however, the significance of the findings remain unclear (PMID:27657681;21598360;25409744). It is absent or not present at a significant frequency in gnomAD. The presence of pathogenic/likely pathogenic missense variant(s) at the same amino acid position indicates that this residue is likely important for protein function. In conclusion, we classify GLA c.1088G>A as a likely pathogenic variant.
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 363 of the GLA protein (p.Arg363His). This variant is present in population databases (rs111422676, gnomAD 0.03%). This missense change has been observed in individual(s) with Fabry disease (PMID: 11668641, 12175777, 26937405, 28302345). ClinVar contains an entry for this variant (Variation ID: 222141). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLA function (PMID: 19387866, 21598360). This variant disrupts the p.Arg363 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12175777, 21598360, 25835592, 26937405; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
This missense variant replaces arginine with histidine at codon 363 of the GLA protein. Functional studies have shown the mutant protein to exhibit significantly reduced GLA enzyme activity in vitro, with a greater than 70% decrease compared to wild type (PMID: 21598360, 23935525). This variant has been reported in four individuals affected with classic Fabry disease and in more than 10 individuals affected with late-onset or non-classical Fabry disease (PMID: 11668641, 12175777, 21420783, 26937405, 28360401, 30477121, 33022387, 33163363, 33204599, 33437642, 34545322, 36624527). In all tested carrier individuals, decreased leukocyte GLA enzyme activities and increased plasma biomarker globotriaosylsphingosine (lyso-Gb3) levels were observed (PMID: 19387866, 21420783, 28302345, 33022387, 34199132). This variant has been identified in 10/183364 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant affecting the same codon, p.Arg363Cys, is considered to be disease-causing (ClinVar variation ID: 198401), suggesting that arginine at this position is important for GLA protein function. Based on the available evidence, this variant is classified as Pathogenic.
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
The p.Arg363His variant in GLA has been reported in at least eight individuals with Fabry disease (PMID: 30477121, 21420783, 11668641, 12175777, 23935525, 28360401, 28302345), segregated with disease in three affected relatives from one family (PMID: 26937405), and has been identified in 0.03% (5/19142) of South Asian chromosomes, including 3 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111422676). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Additionally, this variant has a high prevalence in late-onset cases, which may account for the frequency in gnomAD. This variant has also been reported in ClinVar as Pathogenic by EGL Genetic Diagnostics and Integrated Genetics (Variation ID: 222141). In vitro functional studies provide some evidence that the p.Arg363His variant may slightly impact protein function (PMID: 21598360, 23935525, 19387866). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of individuals hemizygous for this variant is highly specific for Fabry disease based on enzymatic diagnosis consistent with disease (PMID: 30477121, 21420783, 11668641, 12175777, 23935525, 28360401, 28302345). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic despite the higher than expected allele frequency in the general population. ACMG/AMP Criteria applied: BS1_supporting, PP1_moderate, PP4, PS3_supporting, PS4_moderate (Richards 2015).
The missense variant p.R363H in GLA (NM_000169.2) has been reported previously in affected individuals with late onset Fabry disease (Blaydon et al 2001; Serebrinsky et al, 2015). In vitro enzyme studies depict a moderate effect on enzyme activity which leads to an attenuated/atypical/late-onset phenotype (Lukas et al, 2013; Riera et al, 2015). I t has been classified as a Pathogenic for the late onset phenotype by the Fabry disease working group (Germain et al,2 020). It has been submitted to ClinVar with conflicting interpretations including VUS/Likely Pathogenic and Pathogenic. It is present in 6 hemizygous males in the gnomAD database. However presence of clinical variability ranging from single organ involvement to ascertainment via family screening could account for the presence of these hemizygous males within the gnomAD database. There is a small physicochemical difference between arginine and histidine, which is not likely to impact secondary protein structure as these residues share similar properties. In silico tools predict the variant to be tolerated and the residue is weakly conserved across species. For these reasons, this variant has been classified as Pathogenic
Variant summary: The GLA c.1088G>A (p.Arg363His) variant involves the alteration of a non-conserved nucleotide. 2/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/88023 control chromosomes (3 hemizygotes) at a frequency of 0.0000341, which does not exceed the estimated maximal expected allele frequency of a pathogenic GLA variant (0.005). This variant has been reported in multiple patients with classic or late-onset Fabry disease. In vitro enyzme activity assay showed this variant led to moderate decrease of enzyme activity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. In addition, p.R363C and p.R363P have been reported to associate with Fabry disease, suggesting R363 is critical for GLA function. Taken together, this variant is classified as pathogenic.
The c.1088G>A (p.Arg363His) variant in the GLA gene is located in the exon 7 of the GLA gene and is predicted to replace arginine with histidine at codon 363 of the GLA protein. This variant has been identified in many individuals with Fabry disease (PMID: 30477121, 21420783, 11668641, 12175777, 28360401, 28302345, 36624527, 34545322, 33437642, 33163363), and reported as segregated with disease in three affected relatives from one family (PMID: 26937405). This variant has been reported to be associated with a later-onset and milder course of disease in males (PMID 26937405, 32161151, 32418857). Biochemical testing in patient lymphoblasts showed reduced enzyme activity of 12% to 24% of normal activity (PMID: 19387866, 21598360, respectively). This variant is rare in the general population according to gnomAD v4.0.0 (0.002%). A different variant affecting the same amino acid residue Arg363 (c.1087C>T, p.Arg363Cys) has been determined to be pathogenic in ClinVar according to ACMG guidelines. Therefore, the c.1088G>A (p.Arg363His) variant in the GLA gene has been classified as pathogenic.
not provided Pathogenic:2Uncertain:1
Cardiovascular phenotype Pathogenic:1
The c.1088G>A (p.R363H) alteration is located in exon 7 (coding exon 7) of the GLA gene. This alteration results from a G to A substitution at nucleotide position 1088, causing the arginine (R) at amino acid position 363 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.005454% (10/183364) total alleles studied, with 6 hemizygote(s) observed. The highest observed frequency was 0.02621% (5/19078) of South Asian alleles. This variant was identified in one or more individuals with features consistent with Fabry disease, often with late onset and/or a renal presentation (Germain, 2020; Politei, 2021; Zenone, 2011; Harale, 2024; external communication), and segregated with disease in at least one family (Serebrinsky, 2015; Delarosa-Rodríguez, 2021). This amino acid position is not well conserved in available vertebrate species. In multiple assays testing GLA function, this variant showed functionally indeterminant results (Lukas, 2013; Wu, 2011). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at