Submissions for variant NM_000169.3(GLA):c.469C>T (p.Gln157Ter)

dbSNP: rs797044702

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000302760	SCV000228801	pathogenic	not provided	2017-11-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000302760	SCV000329661	pathogenic	not provided	2017-04-21	criteria provided, single submitter	clinical testing	The Q157X pathogenic variant in the GLA gene has been reported in multiple individuals with Fabry disease (Eng et al., 1994; Shabbeer et al., 2005; Schafer et al., 2005; Johnson et al., 2013). In addition, Q157X has been classified as a pathogenic variant by another clinical laboratory in ClinVar (SCV000228801.1; Landrum et al., 2016). Q157X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Functional studies show the Q157X pathogenic variant results in increased levels of lyso-globotriaosylsphingosine, a biomarker for Fabry disease (Lukas et al., 2013). Other nonsense variants in the GLA gene have been reported in HGMD in association with Fabry disease (Stenson et al., 2014). Furthermore, the Q157X pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Q157X in the GLA gene is interpreted as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001384489	SCV001583998	pathogenic	Fabry disease	2023-03-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln157*) in the GLA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Fabry disease (PMID: 7531540, 16595074, 18849176, 23935525). ClinVar contains an entry for this variant (Variation ID: 196225).
Revvity Omics, Revvity	RCV000302760	SCV002024330	pathogenic	not provided	2019-06-16	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001384489	SCV002054432	pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326971	SCV002633927	pathogenic	Cardiovascular phenotype	2022-04-29	criteria provided, single submitter	clinical testing	The p.Q157* pathogenic mutation (also known as c.469C>T), located in coding exon 3 of the GLA gene, results from a C to T substitution at nucleotide position 469. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This variant has been detected in several individuals reported to have Fabry disease (FD) or features consistent with FD, including reported de novo occurrences (Eng CM et al. Hum Mol Genet, 1994 Oct;3:1795-9; Eng CM et al. Mol Med, 1997 Mar;3:174-82; Schäfer E et al. Hum Mutat, 2005 Apr;25:412; Shabbeer J et al. Hum Genomics, 2006 Mar;2:297-309; Erdos M et al. Mol Genet Metab, 2008 Dec;95:224-8; Johnson B et al. Ann Lab Med, 2013 Jul;33:274-8; Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632; Jain R et al. JACC Cardiovasc Imaging, 2018 Apr;11:644-647). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
All of Us Research Program, National Institutes of Health	RCV001384489	SCV004822609	pathogenic	Fabry disease	2023-07-09	criteria provided, single submitter	clinical testing	The c.469C>T (p.Gln157*) variant of the GLA gene is located in exon 3 and is predicted to cause loss of normal protein function either through abnormal, prematurely truncated protein, or by absence of protein product due to nonsense-mediated mRNA decay. The loss-of-function variants in GLA gene are known to be pathogenic for Fabry disease (PMID: 10666480, 12175777). This variant has been identified in individuals with Fabry disease (PMID: 7531540, 16595074, 18849176). This variant has not been identified in the general population according to gnomAD. For these reasons, the c.469C>T (p.Gln157*) variant in the GLA gene has been classified as pathogenic.