rs869312141
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000169.3(GLA):c.272T>C(p.Ile91Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I91N) has been classified as Pathogenic.
Frequency
Consequence
NM_000169.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLA | NM_000169.3 | c.272T>C | p.Ile91Thr | missense_variant | 2/7 | ENST00000218516.4 | |
RPL36A-HNRNPH2 | NM_001199973.2 | c.301-8028A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLA | ENST00000218516.4 | c.272T>C | p.Ile91Thr | missense_variant | 2/7 | 1 | NM_000169.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 23
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 05, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 19, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2022 | Published functional studies demonstrate a significantly reduced enzyme activity compared to wildtype activity (Ishii et al., 2007; Park et al., 2009; Wu et al., 2011; Lukas et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25655062, 27356758, 27560961, 28723748, 29853467, 25382311, 34679477, 27916943, 33714629, 34922431, 9100224, 17555407, 21598360, 23935525, 26415523, Cai2012, Monte2022, Carnicer-Caceres2022, 32023956, 33915609, 19387866, 33922740, 17894781, 20505683, 23430946, 30477121, 30099469, 19287194) - |
Fabry disease Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 13, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GLA function (PMID: 17555407, 21598360, 26415523). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 222204). This missense change has been observed in individuals with Fabry disease (PMID: 9100224, 19287194, 23935525, 27560961). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 91 of the GLA protein (p.Ile91Thr). - |
GLA-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 21, 2023 | The GLA c.272T>C variant is predicted to result in the amino acid substitution p.Ile91Thr. This variant was reported in multiple individuals with Fabry disease (Eng et al. 1997. PubMed ID: 9100224; Ishii et al. 2007. PubMed ID: 17555407; Park et al. 2009. PubMed ID: 19287194; Wu et al. 2011. PubMed ID: 21598360; Lukas et al. 2013. PubMed ID: 23935525; Duro et al. 2018. PubMed ID: 30477121; Pan et al. 2016. PubMed ID: 27560961; Goicoechea et al. 2021. PubMed ID: 33714629). In vitro functional studies show that this variant results in absent or severely reduced alpha-galactosidase A enzymatic activity (Figure 1, Park et al. 2009. PubMed ID: 19287194; Table 1, Wu et al. 2011. PubMed ID: 21598360). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at