ClinVar Miner

Submissions for variant NM_001184880.2(PCDH19):c.2656C>T (p.Arg886Ter)

dbSNP: rs756414485
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188378 SCV000241990 pathogenic not provided 2019-10-14 criteria provided, single submitter clinical testing Previously reported to segregate with epilepsy in several females from a single family who had febrile, generalized, and/or focal seizures, one of whom also had cognitive delay (Depienne et al., 2011); 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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23334464, 22267240, 25525159, 21053371, 27179713, 23712037, 22633638, 29377098)
Athena Diagnostics Inc RCV000188378 SCV000614416 pathogenic not provided 2017-02-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV002426910 SCV002744083 pathogenic Inborn genetic diseases 2019-06-14 criteria provided, single submitter clinical testing The p.R886* pathogenic mutation (also known as c.2656C>T), located in coding exon 4 of the PCDH19 gene, results from a C to T substitution at nucleotide position 2656. This changes the amino acid from an arginine to a stop codon within coding exon 4. This variant has been reported in 5 females with seizures, including one family with 4 affected women (Depienne C et al. Hum. Mutat., 2011 Jan;32:E1959-75; Smith L et al. Epilepsia, 2018 03;59:679-689). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV002517880 SCV002943715 pathogenic Developmental and epileptic encephalopathy, 9 2024-01-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg886*) in the PCDH19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH19 are known to be pathogenic (PMID: 21053371). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with generalized epilepsy with febrile seizures plus (PMID: 21053371). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 206341). For these reasons, this variant has been classified as Pathogenic.

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