Submissions for variant NM_000169.3(GLA):c.1181T>C (p.Leu394Pro)

gnomAD frequency: 0.00002  dbSNP: rs886044779

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000316758	SCV000332577	uncertain significance	not provided	2015-06-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001183037	SCV001348687	uncertain significance	Fabry disease	2023-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 394 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies investigating the impact of this variant on GLA enzyme activity have not been reported. This variant has been reported in a female affected with Fabry disease (PMID: 32719972), in a child with unspecified gender affected with Fabry disease (PMID: 33073010), and in an individual affected with isolated left bundle branch block (PMID: 33835496). However, the variant has been reported in males lacking Fabry disease symptoms in multiple pedigrees affected with kidney disease (doi:10.1101/2022.09.27.509714; not peer-reviewed), suggesting that the variant may not be causative for Fabry disease. This variant has also been observed in additional individuals unaffected with Fabry disease and has not been observed in affected individuals (communication with external laboratories; ClinVar SCV ID: SCV001513189.3, SCV001982529.3, SCV003816826.1; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001183037	SCV001513189	uncertain significance	Fabry disease	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 394 of the GLA protein (p.Leu394Pro). 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: 281678). 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 with a negative predictive value of 80%. 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.
GeneDx	RCV000316758	SCV001982529	uncertain significance	not provided	2022-06-22	criteria provided, single submitter	clinical testing	In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); Identified in a female patient with left bundle branch block aberrancy who also harbored variants in the NKX2-5 and ALMS1 genes (Kohli et al., 2021); This variant is associated with the following publications: (PMID: 33835496)
Genome-Nilou Lab	RCV001183037	SCV002054340	uncertain significance	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002328756	SCV002634485	uncertain significance	Cardiovascular phenotype	2020-03-26	criteria provided, single submitter	clinical testing	The p.L394P variant (also known as c.1181T>C), located in coding exon 7 of the GLA gene, results from a T to C substitution at nucleotide position 1181. The leucine at codon 394 is replaced by proline, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV001183037	SCV002776640	uncertain significance	Fabry disease	2021-11-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000316758	SCV003816826	uncertain significance	not provided	2022-11-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001183037	SCV004838990	uncertain significance	Fabry disease	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 394 of the GLA protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. Functional studies investigating the impact of this variant on GLA enzyme activity have not been reported. This variant has been reported in a female affected with Fabry disease (PMID: 32719972), in a child with unspecified gender affected with Fabry disease (PMID: 33073010), and in an individual affected with isolated left bundle branch block (PMID: 33835496). However, the variant has been reported in males lacking Fabry disease symptoms in multiple pedigrees affected with kidney disease (doi:10.1101/2022.09.27.509714; not peer-reviewed), suggesting that the variant may not be causative for Fabry disease. This variant has also been observed in additional individuals unaffected with Fabry disease and has not been observed in affected individuals (communication with external laboratories; ClinVar SCV ID: SCV001513189.3, SCV001982529.3, SCV003816826.1; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.
Natera, Inc.	RCV001183037	SCV002081331	uncertain significance	Fabry disease	2021-09-27	no assertion criteria provided	clinical testing