chrX-101398504-T-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 4P and 7B. PM1PM5BP4_ModerateBP6BS2
The NM_000169.3(GLA):c.865A>G(p.Ile289Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,206,911 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I289F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000169.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLA | NM_000169.3 | c.865A>G | p.Ile289Val | missense_variant | 6/7 | ENST00000218516.4 | |
RPL36A-HNRNPH2 | NM_001199973.2 | c.300+3047T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLA | ENST00000218516.4 | c.865A>G | p.Ile289Val | missense_variant | 6/7 | 1 | NM_000169.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000982 AC: 11AN: 112019Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5AN XY: 34191
GnomAD3 exomes AF: 0.000158 AC: 29AN: 183467Hom.: 0 AF XY: 0.000133 AC XY: 9AN XY: 67903
GnomAD4 exome AF: 0.0000274 AC: 30AN: 1094836Hom.: 0 Cov.: 30 AF XY: 0.0000222 AC XY: 8AN XY: 360252
GnomAD4 genome ? AF: 0.0000892 AC: 10AN: 112075Hom.: 0 Cov.: 23 AF XY: 0.000175 AC XY: 6AN XY: 34257
ClinVar
Submissions by phenotype
Fabry disease Uncertain:3Benign:3
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | 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). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 23, 2023 | This missense variant replaces isoleucine with valine at codon 289 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).One 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. - |
Uncertain significance, no assertion criteria provided | research | Albrecht-Kossel-Institute, Medical University Rostock | Jan 01, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Benign, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | 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). - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | - - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 14, 2018 | This variant is associated with the following publications: (PMID: 26415523, 27916943) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 25, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2017 | 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 29, 2020 | 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. - |
Migalastat response Other:1
drug response, no assertion criteria provided | research | Albrecht-Kossel-Institute, Medical University Rostock | Jan 01, 2014 | - Pharmacological Chaperone response: yes |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at