Submissions for variant NM_004519.4(KCNQ3):c.1709T>C (p.Met570Thr)

gnomAD frequency: 0.00001  dbSNP: rs199999939

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000712132	SCV000241583	uncertain significance	not provided	2018-07-12	criteria provided, single submitter	clinical testing	p.Met570Thr (ATG>ACG): c.1709 T>C in exon 13 of the KCNQ3 gene (NM_004519.2) The M570T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The M570T variant 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 that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, 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 EPILEPSY panel(s).
Athena Diagnostics Inc	RCV000712132	SCV000842554	uncertain significance	not provided	2018-07-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001162487	SCV001324442	uncertain significance	Seizures, benign familial neonatal, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000712132	SCV001746971	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Invitae	RCV001852470	SCV002149560	uncertain significance	Benign neonatal seizures	2022-06-05	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 570 of the KCNQ3 protein (p.Met570Thr). This variant is present in population databases (rs199999939, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of KCNQ3-related conditions (PMID: 32086284). ClinVar contains an entry for this variant (Variation ID: 205975). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV002399698	SCV002713507	uncertain significance	Inborn genetic diseases	2018-07-27	criteria provided, single submitter	clinical testing	The p.M570T variant (also known as c.1709T>C), located in coding exon 13 of the KCNQ3 gene, results from a T to C substitution at nucleotide position 1709. The methionine at codon 570 is replaced by threonine, an amino acid with similar properties. In one study of Rolandic epilepsy, this variant was detected in one of 567 controls, but absent in 194 patients (Bobbili DR et al. Eur. J. Hum. Genet., 2018 Feb;26:258-264). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.