ClinVar Miner

Submissions for variant NM_001077350.3(NPRL3):c.1270C>T (p.Arg424Ter)

gnomAD frequency: 0.00001  dbSNP: rs886037961
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000241508 SCV001213929 pathogenic Epilepsy, familial focal, with variable foci 3 2024-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg424*) in the NPRL3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPRL3 are known to be pathogenic (PMID: 26285051, 26505888). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with focal epilepsy (PMID: 27173016). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 254360). For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000241508 SCV001994779 pathogenic Epilepsy, familial focal, with variable foci 3 2021-10-18 criteria provided, single submitter clinical testing
GeneDx RCV002281079 SCV002569770 pathogenic not provided 2023-05-08 criteria provided, single submitter clinical testing Reported previously in an individual with refractory focal epilepsy (Abumurad et al., 221); 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); This variant is associated with the following publications: (PMID: 34868250, 34693554, 33461085, 33741238, 30093711, 27173016, 30485578, 36864519, 37099548, 34235417, 36937533)
Neuberg Centre For Genomic Medicine, NCGM RCV000241508 SCV004801335 likely pathogenic Epilepsy, familial focal, with variable foci 3 criteria provided, single submitter clinical testing The stop gained variant c.1270C>T(p.Arg424Ter) in NPRL3 gene has been reported in heterozygous state in individuals with focal epilepsy (Weckhuysen S, et al., 2016, Abumurad S, et al., 2021). The variant is novel (not in any individuals) in gnomAD Exomes and in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Ricos MG, et al., 2016). For these reasons, this variant has been classified as Likely Pathogenic.
OMIM RCV000241508 SCV000299385 pathogenic Epilepsy, familial focal, with variable foci 3 2016-09-21 no assertion criteria provided literature only

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