ClinVar Miner

Submissions for variant NM_004519.4(KCNQ3):c.950T>C (p.Ile317Thr)

dbSNP: rs1586800133
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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 RCV000818357 SCV000958967 pathogenic Benign neonatal seizures 2024-06-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 317 of the KCNQ3 protein (p.Ile317Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant benign familial neonatal seizures (PMID: 24375629; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 661030). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNQ3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCNQ3 function (PMID: 24375629). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853346 SCV000996208 pathogenic Seizures, benign familial neonatal, 2 2018-10-24 criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in three related individuals with neonatal seizures (all 3 tested individuals), and additionally, febrile seizures and cognitive impairment (2 out of 3 tested individuals) (PMID: 24375629). This variant is located in the S5-S6 linker, one residue upstream of the GYG sequence of the selectivity filter. In vitro functional testing of this variant using patch-clamping of transfected CHO cells demonstrated that this variant confers decreased current density (PMID: 24375629). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.950T>C (p.Ile317Thr) variant on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.950T>C (p.Ile317Thr) variant is classified as pathogenic.
PreventionGenetics, part of Exact Sciences RCV003413649 SCV004112994 likely pathogenic KCNQ3-related disorder 2022-11-13 criteria provided, single submitter clinical testing The KCNQ3 c.950T>C variant is predicted to result in the amino acid substitution p.Ile317Thr. This variant was reported in three individuals from a family, segregating with neonatal seizures in all three individuals and febrile seizures and cognitive impairment in two family members (Soldovieri et al 2014. PubMed ID: 24375629). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant occurs in a conserved position of the ion channel selectivity filter, and functional studies suggested it is deleterious (Soldovieri et al 2014. PubMed ID: 24375629). This variant is interpreted as likely pathogenic.
GeneDx RCV004773192 SCV005384143 pathogenic not provided 2024-04-24 criteria provided, single submitter clinical testing Identified in affected individuals from a single family with benign familial neonatal seizures in published literature (PMID: 24375629); Published functional studies demonstrate p.(I317T) has a functionally abnormal effect on channel function (PMID: 24375629); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31440721, 28717674, 24375629)
GeneReviews RCV000853346 SCV002061349 not provided Seizures, benign familial neonatal, 2 no assertion provided literature only Moderate psychomotor delay in some family members

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