X-101403933-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_000169.3(GLA):c.247G>A(p.Asp83Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,207,559 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D83D) has been classified as Likely benign.
Frequency
Consequence
NM_000169.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLA | NM_000169.3 | c.247G>A | p.Asp83Asn | missense_variant | 2/7 | ENST00000218516.4 | |
RPL36A-HNRNPH2 | NM_001199973.2 | c.301-8003C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLA | ENST00000218516.4 | c.247G>A | p.Asp83Asn | missense_variant | 2/7 | 1 | NM_000169.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000888 AC: 1AN: 112649Hom.: 0 Cov.: 23 AF XY: 0.0000287 AC XY: 1AN XY: 34795
GnomAD3 exomes AF: 0.0000218 AC: 4AN: 183388Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67824
GnomAD4 exome AF: 0.0000402 AC: 44AN: 1094910Hom.: 0 Cov.: 29 AF XY: 0.0000333 AC XY: 12AN XY: 360392
GnomAD4 genome AF: 0.00000888 AC: 1AN: 112649Hom.: 0 Cov.: 23 AF XY: 0.0000287 AC XY: 1AN XY: 34795
ClinVar
Submissions by phenotype
Fabry disease Uncertain:6
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 83 of the GLA protein (p.Asp83Asn). This variant is present in population databases (rs782722577, gnomAD 0.005%). This missense change has been observed in individual(s) with reduced alpha-galactosidase activity on screening tests and/or individuals affected with stroke (PMID: 23306324, 23935525, 24365053, 26070511). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (PMID: 26070511). ClinVar contains an entry for this variant (Variation ID: 222202). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GLA function (PMID: 27657681). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2023 | This missense variant replaces aspartic acid with asparagine at codon 83 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. A functional study has shown that this variant results in slightly reduced GLA enzyme activity (PMID: 27657681). This variant has been reported in two female affected with heart diseases (PMID: 24496231, 29227985), two individuals affected with stroke (PMID: 23306324, 23935525, 26070511), and in one female affected with kidney disease (PMID: 24365053). GLA enzyme activity or Gb3 levels were reported to be normal in some of these patients (PMID: 24496231, 26070511, 29227985), as well as abnormal in a few others (PMID: 23306324, 24365053). This variant has also been reported in hemizygous state in one patient's brother, who showed no manifestations of Fabry disease, and had normal plasma and leukocyte GAL enzyme activities (PMID: 26070511). This variant has been identified in 4/183388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces aspartic acid with asparagine at codon 83 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant results in slightly reduced GLA enzyme activity (PMID: 27657681). This variant has been reported in two individuals affected with heart diseases (PMID: 24496231, 29227985), two individuals affected with stroke (PMID: 23306324, 23935525, 26070511), and in one female affected with kidney disease (PMID: 24365053). GLA enzyme activity or Gb3 levels were reported to be normal in some of these patients (PMID: 24496231, 26070511, 29227985), as well as abnormal in a few others (PMID: 23306324, 24365053). This variant has also been reported in hemizygous state in one patient's brother, who showed no manifestations of Fabry disease, and had normal plasma and leukocyte GAL enzyme activities (PMID: 26070511). This variant has been identified in 4/183388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:3Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 14, 2016 | - - |
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Sep 22, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 28, 2019 | See Variant Classification Assertion Criteria. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 22, 2022 | The p.D83N variant (also known as c.247G>A), located in coding exon 2 of the GLA gene, results from a G to A substitution at nucleotide position 247. The aspartic acid at codon 83 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been identified in cohorts of subjects with stroke, heart disease and kidney disease (Lukas J et al. PLoS Genet., 2013 Aug;9:e1003632; Herrera J et al. Clin. Nephrol., 2014 Feb;81:112-20; Ferreira S et al. Clin. Chim. Acta, 2015 Jul;447:96-104; Schiffmann R et al. Genet. Med., 2018 07;20:754-759). One female subject with stroke was noted to carry this alteration, but the alteration was also noted in her unaffected brother (Ferreira S et al. Clin. Chim. Acta, 2015 Jul;447:96-104). Based on data from gnomAD, the A allele has an overall frequency of 0.0022% (4/183388) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.0049% (4/81872) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at