Submissions for variant NM_000169.3(GLA):c.1055C>G (p.Ala352Gly)

gnomAD frequency: 0.00001  dbSNP: rs869312162

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000606004	SCV000731441	uncertain significance	not specified	2019-06-28	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV000209785	SCV001351145	uncertain significance	Fabry disease	2022-10-20	criteria provided, single submitter	clinical testing	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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000209785	SCV001422926	uncertain significance	Fabry disease	2020-01-22	criteria provided, single submitter	curation	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).
GeneDx	RCV001589083	SCV001824166	uncertain significance	not provided	2020-11-13	criteria provided, single submitter	clinical testing	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)
Genome-Nilou Lab	RCV000209785	SCV002054343	uncertain significance	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Invitae	RCV000209785	SCV003477874	pathogenic	Fabry disease	2024-01-30	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000606004	SCV003844678	uncertain significance	not specified	2023-10-27	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV001589083	SCV004235152	uncertain significance	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Albrecht-Kossel-Institute, Medical University Rostock	RCV000209785	SCV000246097	uncertain significance	Fabry disease	2014-01-01	no assertion criteria provided	research
Albrecht-Kossel-Institute, Medical University Rostock	RCV000209219	SCV000246098	drug response	Migalastat response	2014-01-01	no assertion criteria provided	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000209785	SCV000863870	likely pathogenic	Fabry disease	2018-05-17	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000209785	SCV001457722	uncertain significance	Fabry disease	2020-09-16	no assertion criteria provided	clinical testing