Total submissions: 14
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000236089 | SCV007590306 | likely benign | not specified | 2026-04-29 | criteria provided, single submitter | clinical testing | Variant summary: GLA c.865A>G (p.Ile289Val) results in a conservative amino acid change in the encoded protein sequence. 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. The variant allele was found at a frequency of 3.3e-05 in 1206911 control chromosomes, predominantly at a frequency of 0.00061 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for disease-causing variants in GLA. c.865A>G has been observed in the presumed heterozygous state in at least 1 female individual(s) affected with clinical features of Fabry disease (Lukas_2016) without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Fabry disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity in vitro (Lukas_2016). The following publication has been ascertained in the context of this evaluation (PMID: 26415523). ClinVar contains an entry for this variant (Variation ID: 217400). Based on the evidence outlined above, the variant was classified as likely benign. |
| Genomenon, |
RCV000209743 | SCV006336401 | likely benign | Fabry disease | 2025-09-19 | criteria provided, single submitter | curation | GLA c.865A>G is a missense variant that changes the amino acid at residue 289 from Isoleucine to Valine. This variant has been observed in at least one proband affected with Fabry disease (PMID:26415523). Functional studies have been reported; however, the significance of the findings remain unclear and/or were performed in patient cells (PMID:26415523). This variant was observed in several healthy hemizygous individuals in gnomAD. In conclusion, we classify GLA c.865A>G as a likely benign variant. |
| Ambry Genetics | RCV002444817 | SCV002683329 | likely benign | Cardiovascular phenotype | 2020-03-29 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Genome- |
RCV000209743 | SCV002054803 | likely benign | Fabry disease | 2021-07-15 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000209743 | SCV001735639 | uncertain significance | Fabry disease | 2024-02-01 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with valine at codon 289 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. One functional study study has shown this variant has little impact on GLA enzyme activity (PMID: 26415523). The same study has also shown normal lysoglobotriaosylceramide levels in a few female individuals who underwent biochemical analysis or genetic testing for Fabry Disease (PMID: 26415523). This variant has been identified in 33/205394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Mayo Clinic Laboratories, |
RCV001507540 | SCV001713145 | uncertain significance | not provided | 2019-09-25 | criteria provided, single submitter | clinical testing | |
| Broad Center for Mendelian Genomics, |
RCV000209743 | SCV001422797 | uncertain significance | Fabry disease | 2020-01-22 | criteria provided, single submitter | curation | The p.Ile289Val variant in GLA has been reported in 4 female individuals with unknown Fabry disease phenotype (PMID: 26415523), and has been identified in 0.096% (27/28054) of Latino chromosomes, including 9 hemizygotes, and 0.032% (6/19042) of African chromosomes, including 2 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140329381). 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 also been reported in ClinVar as a VUS by GeneDx, the Laboratory for Molecular Medicine, and the Albrecht-Kossel-Institute, and as likely benign and benign by Invitae and the Swiss Institute of Bioinformatics, respectively (ID: 217400). In vitro functional studies provide some evidence that the p.Ile289Val 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. One additional pathogenic variant, causing a different amino acid change at the same position, p.Ile289Phe, has been reported in association with Fabry disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 21598360, 10666480/Variation ID: 92568). In summary, while the clinical significance of the p.Ile289Val variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, PM5_supporting, BS3_supporting (Richards 2015). |
| SIB Swiss Institute of Bioinformatics | RCV000209743 | SCV000803618 | benign | Fabry disease | 2018-05-31 | criteria provided, single submitter | curation | This variant is interpreted as a Benign, for Fabry disease, in X-linked Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:26415523). |
| Labcorp Genetics |
RCV000209743 | SCV000622194 | likely benign | Fabry disease | 2025-11-22 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000236089 | SCV000539243 | uncertain significance | not specified | 2017-01-24 | criteria provided, single submitter | clinical testing | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in one patient with Fabry disease. It is present in ExAC with a Max MAF of 0.11% in Latino chrs (with 2 hemizygotes). It's been seen in 1 female with symptoms of Fabry disease. It is classified in ClinVar with 1 star as VUS by GeneDx and Albrecht-Kossel-Institute,Medical University Rostock. |
| Gene |
RCV001507540 | SCV000294058 | likely benign | not provided | 2018-11-14 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 26415523, 27916943) |
| Prevention |
RCV004752792 | SCV005348501 | uncertain significance | GLA-related disorder | 2024-03-29 | no assertion criteria provided | clinical testing | The GLA c.865A>G variant is predicted to result in the amino acid substitution p.Ile289Val. This variant was reported in a female undergoing biochemical or genetic testing for Fabry disease (Table 1, Lukas et al. 2016. PubMed ID: 26415523). In vitro analysis has shown 80% of residual enzyme activity (Table 1, Lukas et al. 2016. PubMed ID: 26415523). Alternative variant at the same codon p.Ile289Phe was reported in patient with classic form of Fabry disease (Topaloglu et al. 1999. PubMed ID: 10666480). In vitro analysis for alternate variants at the same codon p.Ile289Ser and p.Ile289Phe have shown residual enzyme activity below detection level (Table S1, Benjamin et al. 2017. PubMed ID:27657681; Table 1, Wu et al. 2011. PubMed ID: 21598360). This variant is reported in 0.096% of alleles in individuals of Latino descent in gnomAD. In Clinvar interpretation of this variant ranges from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/217400/). At this time, the clinical significance of p.Ile289Val variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Albrecht- |
RCV000209181 | SCV000246078 | drug response | Migalastat response | 2014-01-01 | no assertion criteria provided | research | |
| Albrecht- |
RCV000209743 | SCV000246077 | uncertain significance | Fabry disease | 2014-01-01 | no assertion criteria provided | research |