Submissions for variant NM_000169.3(GLA):c.616C>T (p.Leu206Phe)

dbSNP: rs730880448

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000624681	SCV000740569	uncertain significance	Primary familial hypertrophic cardiomyopathy	2017-05-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860416	SCV002200740	uncertain significance	Fabry disease	2022-03-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 206 of the GLA protein (p.Leu206Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GLA-related conditions. ClinVar contains an entry for this variant (Variation ID: 520522). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002358744	SCV002654534	uncertain significance	Cardiovascular phenotype	2024-08-07	criteria provided, single submitter	clinical testing	The p.L206F variant (also known as c.616C>T), located in coding exon 4 of the GLA gene, results from a C to T substitution at nucleotide position 616. The leucine at codon 206 is replaced by phenylalanine, an amino acid with highly similar properties. A different variant affecting this codon (p.L206P, c.617T>C) has been reported in association with Fabry disease (Pan X et al. PLoS ONE, 2016 Aug;11:e0161330; Kim JH et al. Korean Circ J, 2017 Mar;47:278-281). This amino acid position is well conserved in available vertebrate species; however, phenylalanine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV001860416	SCV002777990	uncertain significance	Fabry disease	2021-10-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001860416	SCV004357521	uncertain significance	Fabry disease	2021-08-31	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 206 of the GLA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001860416	SCV005426151	uncertain significance	Fabry disease	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 206 of the GLA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.