ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.639+919G>A (rs199473684)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics, RCV000728949 SCV000927901 pathogenic not provided 2018-08-31 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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000728949 SCV000856576 pathogenic not provided 2017-08-24 criteria provided, single submitter clinical testing
GeneReviews RCV000154318 SCV000494669 pathogenic Fabry disease 2017-01-05 no assertion criteria provided literature only
Invitae RCV000154318 SCV000748692 pathogenic Fabry disease 2018-07-05 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154318 SCV000203980 pathogenic Fabry disease 2014-10-07 criteria provided, single submitter clinical testing The c.639+919G>A variant in GLA (also referred to as c.640-801G>A) has been reported in 6 individuals with a later-onset, cardiac variant Fabry disease and in multiple individuals with HCM or LVH, all of which exhibited reduced GLA enzyme activity levels (Ishii 2002, Lin 2009, Lin 2010). Additionally, this variant was absent from 528 control chromosomes tested in two studies (Ishii 2002, Hwu 2009). This variant has been previously identified by our laboratory in 2 Asian individuals with HCM, and segregated in 3 affected relatives (2 with Fabry disease and 1 with reduced GLA activity). Finally, molecular studies demonstrated 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). In summary, the c.639+919G>A variant meets our criteria to be classified as pathogenic based on its presence in clinically affected individuals, absence from controls, segregation studies and functional evidence.
OMIM RCV000011515 SCV000031747 uncertain significance Fabry disease, cardiac variant 2002-04-01 no assertion criteria provided literature only

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