Submissions for variant NM_004519.4(KCNQ3):c.1421C>T (p.Thr474Met)

gnomAD frequency: 0.00001  dbSNP: rs757583944

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187976	SCV000241579	uncertain significance	not provided	2014-06-11	criteria provided, single submitter	clinical testing	p.Thr474Met (ACG>ATG): c.1421 C>T in exon 10 of the KCNQ3 gene (NM_004519.2) A variant of unknown significance has been identified in the KCNQ3 gene. The T474M variant 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. It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position in the C-terminal domain of the protein that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense mutations have not been reported in this region of the protein. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Invitae	RCV001069993	SCV001235199	uncertain significance	Benign neonatal seizures	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 474 of the KCNQ3 protein (p.Thr474Met). This variant is present in population databases (rs757583944, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of KCNQ3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 205971). 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%. 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.
Illumina Laboratory Services, Illumina	RCV001159603	SCV001321327	benign	Seizures, benign familial neonatal, 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.