Submissions for variant NM_000169.3(GLA):c.640-801G>A

gnomAD frequency: 0.00005  dbSNP: rs199473684

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844706	SCV000203980	pathogenic	Fabry disease; Hypertrophic cardiomyopathy	2018-04-03	criteria provided, single submitter	clinical testing	The c.639+919G>A variant in GLA (also described as c.640-801G>A in the literatur e) has been reported in at least 6 individuals with a later-onset, cardiac varia nt of Fabry disease (Ishii 2002) and in many individuals with hypertrophic cardi omyopathy (HCM) or left ventricular hypertrophy (LVH), all of whom exhibited red uced GLA enzyme activity levels (Ishii 2002, Lin 2009, Lin 2010, Hsu 2016, Kubo 2017). This variant has also been identified by our laboratory in 4 Asian indivi duals with HCM or Fabry disease, and segregated with disease in 3 affected relat ives (2 with Fabry disease and 1 with reduced GLA activity). This variant has be en also been identified in 1/1041 of Asian chromosomes (a hemizygous male) by th e Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs199473684). Functional studies have shown that the c.639+919G>A variant result s in the accumulation of lamellar bodies and glycosphingolipids in induced pluri potent stem cell cardiomyocytes from a patient with Fabry disease (Chou 2017). I n addition, mRNA slicing studies have shown that this variant leads to abnormal splicing, resulting in the introduction of an additional 57 nucleotides into the GLA transcript, ultimately leading to a truncated protein (Ischii 2002, Palhais 2016, Chang 2017). In summary, the c.639+919G>A variant meets criteria to be cl assified as pathogenic for Fabry disease in an X-linked manner based upon presen ce in multiple affected individuals, functional and segregation studies. ACMG/AM P Criteria applied (Richards 2015): PS3; PS4; PP1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000154318	SCV000748692	pathogenic	Fabry disease	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the GLA gene. It does not directly change the encoded amino acid sequence of the GLA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs199473684, gnomAD 0.1%). This variant has been observed in individual(s) with Fabry disease and hypertrophic cardiomyopathy (PMID: 11828341, 19621417, 20031620, 22437327, 25611685). It is commonly reported in individuals of Taiwanese ancestry (PMID: 27931613). This variant is also known as IVS4+919G>A. ClinVar contains an entry for this variant (Variation ID: 10768). Studies have shown that this variant results in insertion of 57bp pseudoexon sequence in intron 4 and introduces a premature termination codon (PMID: 11828341, 27595546, 28430823). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000728949	SCV000856576	pathogenic	not provided	2017-08-24	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769537	SCV000900932	pathogenic	Cardiomyopathy	2023-05-03	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000728949	SCV000927901	pathogenic	not provided	2018-08-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000154318	SCV001422791	pathogenic	Fabry disease	2024-08-05	criteria provided, single submitter	curation	The c.639+919G>A variant in GLA has been reported in many individuals with a later-onset cardiac phenotype of Fabry disease, segregated with disease in 3 affected relatives from 1 family (PMID:29215092, 25611685, 22437327,19621417, 20821055, 20031620,11828341), and has been identified in 0.05% (2/3599) of East Asian chromosomes, including a single hemizygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199473684). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Pathogenic variants may be present at a low frequency in the general population, for diseases with clinical variability, or reduced penetrance. This variant has also been reported in ClinVar (Variation ID: ) and has been interpreted as pathogenic by multiple submitters. RNAseq analysis performed on affected tissues shows that the c.639+919G>A variant creates alternative splicing in the majority of transcripts, leading to an in-frame cryptic exon that includes a stop codon and results in a truncated or absent protein. The phenotype of individuals hemizygous for this variant is highly specific for Fabry disease based on the classic phenotype consistent with disease (PMID: 25611685, 22437327,19621417, 20821055, 20031620,11828341). In summary, this variant meets criteria to be classified as pathogenic for X-linked Fabry disease. ACMG/AMP Criteria applied: PS4, PVS1_strong, PP1, PP4 (Richards 2015).
Color Diagnostics, LLC DBA Color Health	RCV000154318	SCV001734431	pathogenic	Fabry disease	2023-05-15	criteria provided, single submitter	clinical testing	This variant is located in intron 4 of the GLA gene and is also known as IVS4+919G>A and c.639+919G>A based on a different transcript NM_000169.2. RNA studies have shown that this variant causes the inclusion of 57 bases from intron 4 as a pseudoexon, resulting in the expression of truncated protein (PMID: 11828341, 27595546, 28430823). These studies have shown that the alternate transcript was present at low levels in most normal tissues and is significantly increased in cells from carrier individuals affected with Fabry disease. This variant has been reported in over forty males of East Asian ancestry affected with mild, late-onset Fabry disease (PMID: 11828341, 20031620, 32246049, 36013057). This variant has also been observed in individuals affected with cardiomyopathy, who showed reduced GLA enzyme activity (PMID: 20031620, 25611685, 30731207, 31028938) and in an individual affected with left ventricular hypertrophy (PMID: 35743592). This variant has been reported to segregate with disease in multiple families affected with Fabry disease or hypertrophic cardiomyopathy (ClinVar SCV000203980.4). Literature has reported the absence of this variant in 230 unaffected control males and 149 unaffected control females (PMID: 11828341, 19621417). This variant has been identified in 1/22077 chromosomes by the Genome Aggregation Database (gnomAD; low coverage region). Large newborn screening studies have shown that this variant is highly prevalent in the Taiwanese population with up to 1/875 males and 1/399 females being carriers (PMID: 19621417, 20031620, 22437327). Mean enzyme activities in the male and female carriers were 23% and 55% of normal mean values, respectively (PMID: 22437327). Loss of GLA function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
GeneDx	RCV000728949	SCV001788703	pathogenic	not provided	2022-06-03	criteria provided, single submitter	clinical testing	Has been reported as a common variant in Taiwanese and Japanese populations in association with reduced GLA enzyme activity levels and Fabry late-onset cardiac phenotype (PMID: 11828341, 22437327, 27931613, 20821055, 30386727); In vitro functional studies have shown that c.640-801 G>A creates a cryptic splice site that causes abnormal gene splicing through introduction of an additional 57 nucleotides into the GLA transcript (PMID: 27595546, 11828341, 28430823); Additional functional studies have shown that this variant is associated with approximately 10% residual alpha-galactosidase activity in patient lymphoblasts (PMID: 11828341); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.639+919 G>A; This variant is associated with the following publications: (PMID: 22437327, 24055776, 19823873, 19621417, 24980630, 25611685, 26869469, 27931613, 28322587, 20821055, 20031620, 28377241, 28430823, 27554049, 29215092, 28082092, 30103270, 30380558, 30386727, 30666049, 30662066, 31956509, 33204599, 32833300, 31447099, 30477121, 32150461, 32246049, 26582918, 11828341, 27595546, 35538921, 33437642, 32843101, 28108302, 28075357)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154318	SCV002014858	pathogenic	Fabry disease	2021-10-11	criteria provided, single submitter	clinical testing	Variant summary: The variant c.640-801G>A is located in intron 4 of the GLA gene. Several in vitro studies demonstrated, that the variant activates a cryptic exon between exon 4 and 5 that results in the insertion of 57 intronic nucleotide, leading to a premature stop codon (Ishii 2002, Chiang 2017, Chang 2017). However, the variant had an incomplete effect on splicing, as the full length product was also detected. Though the truncated variant-protein had no enzyme activity (Ishii 2002), since the normal transcript was also present, it resulted in some residual enzyme activity in samples from male individuals carrying the variant (Ishii 2002, Lin 2010, Chien 2012, Chang 2017). The variant allele was found in 1/22077 control chromosomes in the genome dataset of gnomAD database (detected in an East Asian individual). c.640-801G>A has been reported in the literature in several individuals affected with the Cardiac Variant of Fabry Disease (FD) (e.g. Ishii 2002, Lin 2010, Hsu 2019), but was also found in controls, especially in East Asian populations, where the variant was observed with a relatively high frequency (~0.0011) in Taiwanese individuals during newborn screening and in healthy adult controls (Chien 2012, Chiang 2017). Though this frequency is higher than predicted for a pathogenic variant in the GLA gene, a recent study indicated that the variant might result in a latent disease progression, with Fabry Disease-associated late onset cardiomyopathy that in many cases can only be detected with more sensitive diagnostic methods or much later in life (Hsu 2019). These authors also suggested that the prevalence of late-onset FD might be much higher than previously expected. In addition, another recent study proposed a multifactorial model, consisting of combinations of multiple variants in conjunction with other organ-related or environmental factors as contributing to the associated cardiac complications and the natural history of disease progression related to this variant (Juang 2019). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; eight classified the variant as likely pathogenic/pathogenic while one classified as VUS. Based on the evidence outlined above, the variant causes a cryptic splice-mutation resulting in decreased enzyme activity, and although it is relatively common in some East Asian subpopulations, it was reported in several individuals with late-onset cardiac FD phenotype; therefore it was classified as pathogenic.
Revvity Omics, Revvity	RCV000728949	SCV002024291	pathogenic	not provided	2023-09-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362578	SCV002658884	pathogenic	Cardiovascular phenotype	2022-07-14	criteria provided, single submitter	clinical testing	The c.640-801G>A intronic pathogenic mutation results from a G to A substitution 801 nucleotides upstream from coding exon 5 in the GLA gene. This alteration (also referred to as IVS4+919G>A, c.936+919G>A or c.639+919G>A in the literature) has been detected in many individuals from Asian populations with reduced alpha-galactosidase A enzyme activity on newborn screen, and has also been detected in adult males and females with reduced enzyme activity reported to have late-onset, primarily cardiac variant Fabry disease with presentation typically after 40 years of age, although the frequency of this variant suggests it exhibits reduced penetrance (Ishii S et al. Am J Hum Genet. 2002;70:994-1002; Hwu WL et al. Hum Mutat. 2009;30:1397-405; Lin HY et al. Circ Cardiovasc Genet. 2009;2:450-6; Lin HY et al. J Inherit Metab Dis. 2010;33:619-24; Chien YH et al. Mol Med. 2012;18:780-4; Hsu TR et al. Orphanet J Rare Dis. 2014;9:96; Kubo T et al. J Cardiol. 2017;69:302-307; Sakuraba H et al. Mol Genet Metab Rep. 2018;17:73-79). In a study of patient-derived induced pluripotent stem cells, cardiomyocytes with this alteration recapitulated the abnormal cardiac phenotype (Chou SJ et al. Int J Cardiol. 2017;232:255-263). This alteration has been demonstrated to result in aberrant splicing, leading to increased expression of a transcript including a portion of intron 4 and the introduction of a premature stop codon (Ishii S et al. Am J Hum Genet. 2002 Apr;70:994-1002; Palhais B et al. Mol Genet Metab. 2016;119:258-269; Chang WH et al. PLoS ONE. 2017;12:e0175929). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
All of Us Research Program, National Institutes of Health	RCV000154318	SCV004839054	pathogenic	Fabry disease	2024-01-08	criteria provided, single submitter	clinical testing	This variant is located in intron 4 of the GLA gene and is also known as IVS4+919G>A and c.639+919G>A based on a different transcript NM_000169.2. RNA studies have shown that this variant causes the inclusion of 57 bases from intron 4 as a pseudoexon, resulting in the expression of truncated protein (PMID: 11828341, 27595546, 28430823). These studies have shown that the alternate transcript was present at low levels in most normal tissues and is significantly increased in cells from carrier individuals affected with Fabry disease. This variant has been reported in over forty males of East Asian ancestry affected with mild, late-onset Fabry disease (PMID: 11828341, 20031620, 32246049, 36013057). This variant has also been observed in individuals affected with cardiomyopathy, who showed reduced GLA enzyme activity (PMID: 20031620, 25611685, 30731207, 31028938) and in an individual affected with left ventricular hypertrophy (PMID: 35743592). This variant has been reported to segregate with disease in multiple families affected with Fabry disease or hypertrophic cardiomyopathy (ClinVar SCV000203980.4). Literature has reported the absence of this variant in 230 unaffected control males and 149 unaffected control females (PMID: 11828341, 19621417). This variant has been identified in 1/22077 chromosomes by the Genome Aggregation Database (gnomAD; low coverage region). Large newborn screening studies have shown that this variant is highly prevalent in the Taiwanese population with up to 1/875 males and 1/399 females being carriers (PMID: 19621417, 20031620, 22437327). Mean enzyme activities in the male and female carriers were 23% and 55% of normal mean values, respectively (PMID: 22437327). Loss of GLA function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
OMIM	RCV000011515	SCV000031747	uncertain significance	Fabry disease, cardiac variant	2002-04-01	flagged submission	literature only
GeneReviews	RCV000154318	SCV000494669	not provided	Fabry disease		no assertion provided	literature only
Natera, Inc.	RCV000154318	SCV002081343	pathogenic	Fabry disease	2020-11-30	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004752698	SCV005348755	pathogenic	GLA-related disorder	2024-07-03	no assertion criteria provided	clinical testing	The GLA c.640-801G>A variant is predicted to interfere with splicing. This variant is an intronic variant that causes alternative splicing (also reported as IVS4+919G>A; Ishii et al. 2002. PubMed ID: 11828341; Palhais et al. 2016. PubMed ID: 27595546; Chang et al. 2017. PubMed ID: 28430823). This variant has been documented in the literature in multiple individuals with Fabry disease, segregates with disease in families, and functional studies support its pathogenicity (see, for example, Lin et al. 2010. PubMed ID: 20821055; Chien et al. 2012. PubMed ID: 22437327; Hsu et al. 2014. PubMed ID: 24980630). This variant is reported in 0.1% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.