Submissions for variant NM_153033.5(KCTD7):c.362G>T (p.Arg121Leu)

gnomAD frequency: 0.00013  dbSNP: rs199624315

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547069	SCV000646352	uncertain significance	Progressive myoclonic epilepsy type 3	2022-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 121 of the KCTD7 protein (p.Arg121Leu). This variant is present in population databases (rs199624315, gnomAD 0.01%). This missense change has been observed in individual(s) with KCTD7-related conditions (PMID: 30295347, 32581362). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 206020). 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: "Benign"; Align-GVGD: "Class C25"). 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	RCV000547069	SCV001326869	uncertain significance	Progressive myoclonic epilepsy type 3	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228821	SCV002511976	uncertain significance	not specified	2024-03-29	criteria provided, single submitter	clinical testing	Variant summary: KCTD7 c.362G>T (p.Arg121Leu) results in a non-conservative amino acid change located in the BTB/POZ domain (IPR000210) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251460 control chromosomes (gnomAD). c.362G>T has been reported in the literature in the compound heterozygous state in two siblings affected with progressive myoclonic epilepsy (Metz_2018), and in at least one other individual, suspected of a neurodevelopmental disorder who was affected with seizures (Turro_2020, Sanchis-Juan_2023). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30295347, 37541188, 32581362). ClinVar contains an entry for this variant (Variation ID: 206020). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics	RCV002453693	SCV002615956	uncertain significance	Inborn genetic diseases	2017-09-12	criteria provided, single submitter	clinical testing	The p.R121L variant (also known as c.362G>T), located in coding exon 3 of the KCTD7 gene, results from a G to T substitution at nucleotide position 362. The arginine at codon 121 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003966	SCV001161975	likely pathogenic	Epileptic encephalopathy		no assertion criteria provided	research