ClinVar Miner

Submissions for variant NM_006545.5(NPRL2):c.100C>T (p.Arg34Ter)

dbSNP: rs886037963
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, University of Leipzig Medical Center RCV000241310 SCV001429424 uncertain significance Epilepsy, familial focal, with variable foci 2 2018-11-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV001266233 SCV001444405 pathogenic Inborn genetic diseases 2018-02-07 criteria provided, single submitter clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000241310 SCV002764810 likely pathogenic Epilepsy, familial focal, with variable foci 2 2021-09-13 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000241310 SCV002767410 uncertain significance Epilepsy, familial focal, with variable foci 2 2023-12-21 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a reported mechanism of disease for a missense variant in this gene (PMID: 31639411) and is associated with familial focal epilepsy, with variable foci 2 (MIM#617116). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Most families with pathogenic variants in this gene have unaffected carriers (PMID: 26505888, PMID: 27173016, PMID: 28199897). (I) 0115 - Variants in this gene are known to have variable expressivity, where intrafamilial variability has been reported (PMID: 27173016). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is located within the first 102 nucleotides of the coding sequence and is predicted to escape nonsense-mediated decay). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0704 - Another truncating variant comparable to the one identified in this case has limited previous evidence for pathogenicity. Truncating variant p.(Ile23Asnfs*6), has been reported in a family with familial focal epilepsy with variable foci. This variant was noted to have incomplete penetrance, with some carriers being unaffected (PMID: 27173016). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic by diagnostic laboratories in ClinVar and has been reported in an additional family with nocturnal frontal lobe epilepsy (PMIDs: 30093711, 33461085). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. Transfected HEK293 cells have demonstrated that this variant had no significant impact on mTORC1 activity. However, authors speculated the assay may not be indicative of an in vivo environment (PMID: 31639411). (I) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx RCV003320623 SCV004025745 pathogenic not provided 2023-02-13 criteria provided, single submitter clinical testing Published functional studies suggest partial loss of function of the variant onmTORC1 repression activity (Dawson et al., 2020); Nonsense 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); Previously reported in association with focal epilepsy (Ricos et al., 2016; Baldassari et al., 2019)); This variant is associated with the following publications: (PMID: 33461085, 30093711, 31639411, 26505888)
OMIM RCV000241310 SCV000299387 pathogenic Epilepsy, familial focal, with variable foci 2 2016-09-21 no assertion criteria provided literature only
Diagnostic Laboratory, Strasbourg University Hospital RCV002274955 SCV002562824 pathogenic Seizure no assertion criteria provided clinical testing

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