rs869312145
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_000169.3(GLA):c.540G>T(p.Leu180Phe) variant causes a missense change involving the alteration of a non-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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. L180L) has been classified as Likely benign.
Frequency
Consequence
NM_000169.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLA | NM_000169.3 | c.540G>T | p.Leu180Phe | missense_variant | 3/7 | ENST00000218516.4 | |
RPL36A-HNRNPH2 | NM_001199973.2 | c.300+6182C>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLA | ENST00000218516.4 | c.540G>T | p.Leu180Phe | missense_variant | 3/7 | 1 | NM_000169.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 22
ClinVar
Submissions by phenotype
Fabry disease Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | research | Albrecht-Kossel-Institute, Medical University Rostock | Jan 01, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 16, 2023 | This missense change has been observed in individual(s) with clinical features of Fabry disease (PMID: 26415523, 31860127). ClinVar contains an entry for this variant (Variation ID: 217387). 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. Experimental studies have shown that this missense change affects GLA function (PMID: 26415523). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 180 of the GLA protein (p.Leu180Phe). - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 22, 2017 | The p.L180F variant (also known as c.540G>T), located in coding exon 3 of the GLA gene, results from a G to T substitution at nucleotide position 540. The leucine at codon 180 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration was reported in a cohort of subjects with Fabry disease and displayed reduced enzyme activity and was shown to be responsive to pharmacologic chaperone treatment (Lukas J et al. Hum. Mutat., 2016 Jan;37:43-51). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
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