Submissions for variant NM_002087.4(GRN):c.388_391del (p.Gln130fs)

dbSNP: rs63749801

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000084442	SCV000613576	pathogenic	not provided	2016-12-07	criteria provided, single submitter	clinical testing
Human Genetics Group at Institute of Prion Diseases London, University College London	RCV000736253	SCV000864550	pathogenic	Frontotemporal dementia	2017-02-01	criteria provided, single submitter	research	frameshift mutations in GRN cause haploinsufficiency and disease. Several mutations at this codon causing deleterious frameshift mutations have been reported on molgen
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513074	SCV003270569	pathogenic	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions; Neuronal ceroid lipofuscinosis 11	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln130Serfs*125) in the GRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GRN are known to be pathogenic (PMID: 16862116, 16950801, 22608501). This variant is present in population databases (rs746629204, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with frontotemporal dementia (PMID: 16862116, 21403024, 31600775). ClinVar contains an entry for this variant (Variation ID: 16011). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000084442	SCV003840808	pathogenic	not provided	2023-04-05	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31361008, 21403024, 30279455, 28473694, 28666471, 17021754, 20045477, 21047645, 32778130, 27036121, 25662776, 20142524, 30112957, 27606344, 21482928, 16862116, 29146050, 31600775, 19158106, 27703466, 26507310, 21908872, 34274995, 21813674, 20975516, 30599136, 33427744, 35650585)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003478976	SCV004222826	pathogenic	GRN-related disorder	2023-11-17	criteria provided, single submitter	clinical testing	Variant summary: GRN c.388_391delCAGT (p.Gln130SerfsX125) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251478 control chromosomes. c.388_391delCAGT has been reported in the literature in individuals affected with Frontotemporal Dementia (e.g. Baker 2006). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 16862116). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000017384	SCV005399417	pathogenic	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neuronal ceroid lipofuscinosis 11 (MIM#614706), primary progressive aphasia (PPA; MIM#607485) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTD; MIM#607485). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal recessive neuronal ceroid lipofuscinosis 11 is very rare. This condition, and autosomal dominant PPA and FTD, have been reported in individuals with missense variants and those resulting in a premature termination codons (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance, where penetrance varies depending on age (OMIM, GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM, GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in multiple heterozygous individuals with non-fluent primary progressive aphasia, Pick's disease or frontotemporal lobar degeneration (ClinVar, PMID: 33427744, PMID: 30599136, PMID: 28473694). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000017384	SCV000037656	pathogenic	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	2006-08-24	no assertion criteria provided	literature only
VIB Department of Molecular Genetics, University of Antwerp	RCV000084442	SCV000116578	not provided	not provided		no assertion provided	not provided