ClinVar Miner

Submissions for variant NM_002087.3(GRN):c.709-2A>G (rs63750548)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000704513 SCV000833465 pathogenic Frontotemporal dementia, ubiquitin-positive; Ceroid lipofuscinosis, neuronal, 11 2018-05-15 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 of the GRN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with frontotemporal dementia (FTD) in several families (PMID: 17334266, 17439980, 18183624), and has also been observed in unrelated individuals affected with FTD (PMID: 17202431, 18183624, 20142524, 21482928, 24494724, 25943890). This variant is also known as g.5913A>G and IVS6–2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 98150). Experimental studies have shown that this variant results in an aberrantly spliced RNA transcript (PMID: 17439980, 18183624). A different variant affecting this nucleotide (c.709-2A>T) has been determined to be pathogenic (PMID: 27258413, 28264768). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GRN are known to be pathogenic (PMID: 16862116, 16950801, 22608501). For these reasons, this variant has been classified as Pathogenic.
VIB Department of Molecular Genetics, University of Antwerp RCV000084453 SCV000116589 not provided not provided no assertion provided not provided

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