Submissions for variant NM_000169.3(GLA):c.540G>T (p.Leu180Phe)

dbSNP: rs869312145

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002345718	SCV002650505	likely pathogenic	Cardiovascular phenotype	2017-05-22	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000209274	SCV004299641	uncertain significance	Fabry disease	2023-07-16	criteria provided, single submitter	clinical testing	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).
Albrecht-Kossel-Institute, Medical University Rostock	RCV000209274	SCV000246047	pathogenic	Fabry disease	2014-01-01	no assertion criteria provided	research
Albrecht-Kossel-Institute, Medical University Rostock	RCV000209663	SCV000246048	drug response	Migalastat response	2014-01-01	no assertion criteria provided	research