Submissions for variant NM_004519.4(KCNQ3):c.2443G>T (p.Asp815Tyr)

gnomAD frequency: 0.00001  dbSNP: rs530506549

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188000	SCV000241603	uncertain significance	not provided	2012-08-31	criteria provided, single submitter	clinical testing	p.Asp815Tyr (GAT>TAT):c.2443 G>T in exon 15 of the KCNQ3 gene (NM_004519.2) The Asp815Tyr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Asp815Tyr in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. This amino acid substitution is non-conservative, as a negatively charged Aspartic acid residue is replaced by a uncharged Tyrosine residue. Asp815Tyr alters a conserved position in the C-terminal region of the protein, and multiple in silico algorithms predict it is damaging to the structure and/or function of the KCNQ3 protein. However, to our knowledge other missense mutations have not been previously reported near Asp815Tyr. Therefore, based on the currently available information, it is unclear whether Asp815Tyr is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000647887	SCV000769691	uncertain significance	Benign neonatal seizures	2024-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 815 of the KCNQ3 protein (p.Asp815Tyr). This variant is present in population databases (rs530506549, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with KCNQ3-related conditions. ClinVar contains an entry for this variant (Variation ID: 205994). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KCNQ3 protein function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228820	SCV002511690	uncertain significance	not specified	2022-04-08	criteria provided, single submitter	clinical testing	Variant summary: KCNQ3 c.2443G>T (p.Asp815Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251294 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2443G>T in individuals affected with Benign Familial Neonatal Seizures 2 and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.