Submissions for variant NM_004519.4(KCNQ3):c.35C>T (p.Ala12Val)

gnomAD frequency: 0.00001  dbSNP: rs796052672

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187961	SCV000241564	likely benign	not specified	2012-08-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806133	SCV000946115	uncertain significance	Benign neonatal seizures	2019-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 12 of the KCNQ3 protein (p.Ala12Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with KCNQ3-related conditions. ClinVar contains an entry for this variant (Variation ID: 205956). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354323	SCV001548913	uncertain significance	not provided		no assertion criteria provided	clinical testing	The KCNQ3 p.Ala12Val variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs796052672) and in ClinVar (classified as likely benign by GeneDx). The variant was identified in control databases in 1 of 4680 chromosomes at a frequency of 0.000214 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: European (non-Finnish) in 1 of 2436 chromosomes (freq: 0.000411), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The p.Ala12 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.