ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.640-801G>A (rs199473684)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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.
Invitae RCV000154318 SCV000748692 pathogenic Fabry disease 2020-09-24 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. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported as a common cause of Fabry disease and hypertrophic cardiomyopathy in Taiwan, although it has also been reported in other populations (PMID: 11828341, 19621417, 20031620, 22437327, 25611685). This variant is also known as IVS4+919G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 10768). Experimental studies have shown that this intronic change results in aberrant RNA splicing (PMID: 11828341, 27595546, 28430823). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2017-07-07 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000728949 SCV000927901 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000154318 SCV001734431 likely pathogenic Fabry disease 2020-08-05 criteria provided, single submitter clinical testing This variant is located in the deep intronic region of intron 4 of the GLA gene. Functional RNA studies have shown that this variant causes the inclusion of 57 bases from intron 4 as pseudoexon, resulting in the expression of a truncated protein (PMID: 11828341, 27595546, 28430823). These studies have shown that alternately spliced transcript was present at low levels in most normal human tissues and is significantly increased in cells from patients with Fabry disease carrying this variant. This variant has been detected in multiple Japanese males affected with late-onset, cardiac variant Fabry disease (PMID: 11828341). Large newborn screening studies have shown that this variant is highly prevalent in the Taiwanese population (PMID: 19621417, 20031620, 22437327) with up to 1/875 males and 1/399 females being carriers (PMID: 22437327). Mean enzyme activities in the male and female carriers were 23% and 55% of normal mean values, respectively (PMID: 22437327). This variant has also been reported in Taiwanese adult males affected with hypertrophic cardiomyopathy (PMID: 20031620, 25611685), who all had reduced GLA enzyme activity. This variant was absent in 528 X-chromosomes from 100 unaffected Japanese males (PMID: 11828341), 130 unaffected Taiwanese males and 149 unaffected Taiwanese females (PMID: 19621417). This variant has been reported in individuals affected with inherited cardiomyopathy (PMID: 30731207, 31028938). In the Genome Aggregation Database (gnomAD), this variant has been identified in 1/22077 chromosomes (1/1000 East Asian chromosomes), but this information may not be reliable due to the low coverage of the region. Loss of GLA function is a known mechanism of disease. Based on available evidence, this variant is classified as Likely Pathogenic.
GeneDx RCV000728949 SCV001788703 pathogenic not provided 2021-03-15 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 (for examples, see Ishii et al., 2002; Lin et al., 2010; Chien et al., 2012; Hsu et al., 2016; Sakuraba et al., 2018; of note, this variant is also reported as c.639+919 G>A due to the use of alternate nomenclature); Has been observed in 1/1000 alleles from individuals of Asian background, including one hemizygous individual, in large population cohorts (Lek et al., 2016); 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 (Ishii et al., 2002; Palhais et al., 2016; Chang et al., 2017); Additional functional studies have shown that this variant is associated with approximately 10% residual alpha-galactosidase activity in patient lymphoblasts (Ishii et al, 2002); Reported in ClinVar as pathogenic (ClinVar Variant ID# 10768; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 33204599, 32246049, 32150461, 31447099, 30477121, 31956509, 30662066, 30666049, 30386727, 30380558, 30103270, 28082092, 29215092, 27554049, 28430823, 28377241, 20031620, 11828341, 20821055, 28322587, 27931613, 26869469, 25611685, 24980630, 19621417, 19823873, 24055776, 22437327, 27595546)
OMIM RCV000011515 SCV000031747 uncertain significance Fabry disease, cardiac variant 2002-04-01 no assertion criteria provided literature only
GeneReviews RCV000154318 SCV000494669 pathogenic Fabry disease 2017-01-05 no assertion criteria provided literature only
Broad Institute Rare Disease Group, Broad Institute RCV000154318 SCV001422791 uncertain significance Fabry disease 2020-01-22 no assertion criteria provided curation The c.639+919G>A variant in GLA has been reported in at least 6 individuals with 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 0.1% (1/1000) 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, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar as a VUS by OMIM and as pathogenic by the Laboratory for Molecular Medicine (Partners Healthcare), Invitae, EGL Clinical Diagnostics, and GeneReviews (ID:10768). In vitro functional studies provide some evidence that the c.639+919G>A variant may impact protein function as a result of alternative splicing and decreased enzyme activity (PMID:11828341, 28430823, 27595546). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of an individual 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, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_moderate, PP1, PP4 (Richards 2015).

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