ClinVar Miner

Submissions for variant NM_004519.4(KCNQ3):c.1226C>G (p.Pro409Arg) (rs149272208)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000725748 SCV000241578 uncertain significance not provided 2013-05-14 criteria provided, single submitter clinical testing p.Pro409Arg (CCT>CGT): c.1226 C>G in exon 8 of the KCNQ3 gene (NM_004519.2) The Pro409Arg missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative as an uncharged non-polar Proline amino acid residue is replaced by a positively charged, polar Arginine residue and the loss of a Proline may affect the secondary structure of the KCNQ3 protein. Pro409Arg alters a highly conserved position in the protein and multiple in-silico algorithms predict it may be damaging to the structure/function of the protein. However, to our knowledge, missense mutations at nearby codons have not been reported previously. Therefore, based on the currently available information, it is unclear whether Pro409Arg is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725748 SCV000339132 uncertain significance not provided 2016-02-15 criteria provided, single submitter clinical testing
Invitae RCV000477245 SCV000543209 uncertain significance Benign familial neonatal seizures 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 409 of the KCNQ3 protein (p.Pro409Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs149272208, ExAC 0.009%). This variant has not been reported in the literature in individuals with KCNQ3-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000765990 SCV000897422 uncertain significance Benign familial neonatal seizures 2 2018-10-31 criteria provided, single submitter clinical testing

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