rs869312162
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2
The NM_000169.3(GLA):āc.1055C>Gā(p.Ala352Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,447 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000169.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLA | NM_000169.3 | c.1055C>G | p.Ala352Gly | missense_variant | 7/7 | ENST00000218516.4 | |
RPL36A-HNRNPH2 | NM_001199973.2 | c.300+2587G>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLA | ENST00000218516.4 | c.1055C>G | p.Ala352Gly | missense_variant | 7/7 | 1 | NM_000169.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 exomes AF: 0.00000546 AC: 1AN: 183231Hom.: 0 AF XY: 0.0000148 AC XY: 1AN XY: 67701
GnomAD4 exome AF: 0.00000364 AC: 4AN: 1097447Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2AN XY: 362811
GnomAD4 genome ? Cov.: 24
ClinVar
Submissions by phenotype
Fabry disease Pathogenic:2Uncertain:5
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Ala352Gly variant in GLA has not been previously reported in individuals with Fabry disease but has been identified in 0.0052% (1/19077) of South Asian chromosomes by the Genome Aggregation Database, including 1 hemizygote (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs869312162). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has been reported in ClinVar as Likely Pathogenic by Sonic Healthcare and as a VUS by the Laboratory for Molecular Medicine and the Albrecht-Kossel-Institute (Variation ID:217410). In vitro functional studies provide some evidence that the p.Ala352Gly variant may not impact protein function (PMID: 26415523). 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. In summary, the clinical significance of the p.Ala352Gly variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, BS3_supporting, PM4 (Richards 2015). - |
Uncertain significance, no assertion criteria provided | research | Albrecht-Kossel-Institute, Medical University Rostock | Jan 01, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | May 17, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 20, 2022 | This missense variant replaces alanine with glycine at codon 352 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). Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. Functional studies support that this variant may not have a significant impact on GLA enzyme activity (PMID: 26415523). This variant has been reported in females affected with Fabry disease (PMID: 32789421). It has also been reported in individuals with suspected but not confirmed Fabry disease (PMID: 26415523, 31860127). This variant has been identified in 1/183231 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 352 of the GLA protein (p.Ala352Gly). This variant is present in population databases (no rsID available, gnomAD 0.005%). This missense change has been observed in individuals with Fabry disease (PMID: 32789421). ClinVar contains an entry for this variant (Variation ID: 217410). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GLA function (PMID: 26415523). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Ala352 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 12920095, 33016649), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 27, 2023 | Variant summary: GLA c.1055C>G (p.Ala352Gly) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183231 control chromosomes. c.1055C>G has been reported in the literature in at-least three unrelated females with end stage renal disease (ESRD) but not any other classic features of Fabry Disease (example, Alhemyadi_2020) and in at-least one individual with a reportedly non-definitive diagnosis of Fabry Disease (example, Balendran_2019). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in approximately 54% of normal activity in-vitro (example, Lukas_2016). The following publications have been ascertained in the context of this evaluation (PMID: 26415523, 27916943, 31860127, 32789421, 34679477). Eight ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014, scoring the variant as uncertain significance (n=7) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 28, 2019 | The p.Ala352Gly variant in GLA has not been previously reported in individuals with clinical features of Fabry disease, but was reported in two individuals with unreported clinical status who were tested for Fabry disease (Lukas 2016). It was also identified in 1/19077 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID #217410). In vitro studies suggest that that this variant has a mild reduction in enzymatic activity (Lukas 2016), but these assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala352Gly variant is uncertain. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 22, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2020 | Reported in patients referred for evaluation of Fabry disease and in patients with unexplained end-stage renal failure (Lukas et al., 2016; Balendran et al., 2020; Alhemyadi et al., 2020); Reported in ClinVar (ClinVar Variant ID# 217410; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies using HEK293 cells demonstrate a high residual enzyme activity (Lukas et al., 2016); This variant is associated with the following publications: (PMID: 26415523, 32789421, 31860127) - |
Migalastat response Other:1
drug response, no assertion criteria provided | research | Albrecht-Kossel-Institute, Medical University Rostock | Jan 01, 2014 | - Pharmacological Chaperone response: no |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at