Submissions for variant NM_000169.3(GLA):c.1024C>T (p.Arg342Ter)

dbSNP: rs104894843

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723730	SCV000110101	pathogenic	not provided	2018-06-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000011491	SCV000283689	pathogenic	Fabry disease	2023-07-13	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 10743). This premature translational stop signal has been observed in individual(s) with Fabry disease (PMID: 8395937, 16595074, 19287194, 20505683, 23980562, 26297554). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg342*) in the GLA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 88 amino acid(s) of the GLA protein. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects GLA function (PMID: 20505683). For these reasons, this variant has been classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000011491	SCV000993561	pathogenic	Fabry disease	2018-12-10	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011491	SCV001363732	pathogenic	Fabry disease	2019-05-13	criteria provided, single submitter	clinical testing	Variant summary: GLA c.1024C>T (p.Arg342X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 182951 control chromosomes (gnomAD). c.1024C>T has been reported in the literature in individuals affected with Fabry Disease (Davies_1993, Lee_2010, Uribe_2015, Rigoldi_2014). These data indicate that the variant is likely to be associated with disease. Patients carrying the variant of interest were found to have 0% GLA activity (Lee_2010, Uribe_2015). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000723730	SCV002024296	pathogenic	not provided	2019-08-06	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000011491	SCV002054382	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000723730	SCV003798845	pathogenic	not provided	2023-01-24	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 88 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28579207, 23980562, 19287194, 8395937, 16595074, 20505683, 11668641, 28723748, 27156739, 11076046, 26297554)
PreventionGenetics, part of Exact Sciences	RCV003398484	SCV004111846	pathogenic	GLA-related disorder	2023-01-31	criteria provided, single submitter	clinical testing	The GLA c.1024C>T variant is predicted to result in premature protein termination (p.Arg342*). This variant has been reported in multiple individuals with classic Fabry disease (Davies et al. 1993. PubMed ID: 8395937; Park et al. 2009. PubMed ID: 19287194; Rigoldi et al. 2013. PubMed ID: 23980562; Uribe et al. 2015. PubMed ID: 26297554; Lee et al. 2010. PubMed ID: 20505683). In patients with this variant the GLA activity in leukocytes was shown to be 0% of the normal GLA enzymatic activity (Uribe et al. 2015. PubMed ID: 26297554; Lee et al. 2010. PubMed ID: 20505683). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in GLA gene are expected to be pathogenic. Although this variant occurs in the last exon and may not result in nonsense mediated decay, other pathogenic variants were reported downstream of this variant. This variant is interpreted as pathogenic.
OMIM	RCV000011491	SCV000031723	pathogenic	Fabry disease	1993-07-01	no assertion criteria provided	literature only
GenomeConnect - Invitae Patient Insights Network	RCV000011491	SCV001749933	not provided	Fabry disease		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 02-05-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.