Submissions for variant NM_153033.5(KCTD7):c.458G>A (p.Arg153His)

gnomAD frequency: 0.00002  dbSNP: rs765235486

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000680019	SCV000827436	likely pathogenic	Progressive myoclonic epilepsy type 3	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 153 of the KCTD7 protein (p.Arg153His). This variant is present in population databases (rs765235486, gnomAD 0.01%). This missense change has been observed in individuals with progressive myoclonic epilepsy (PMID: 30295347, 31216804, 34469883, 36034301). ClinVar contains an entry for this variant (Variation ID: 561040). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCTD7 protein function. This variant disrupts the p.Arg153 amino acid residue in KCTD7. Other variant(s) that disrupt this residue have been observed in individuals with KCTD7-related conditions (PMID: 34866617), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Children’s Center Hospital, Tehran University of Medical Sciences	RCV000680019	SCV001430884	affects	Progressive myoclonic epilepsy type 3	2019-02-25	criteria provided, single submitter	clinical testing	Non-Syndromic Epileptic Encephalopathies (NS-EE)
CeGaT Center for Human Genetics Tuebingen	RCV002512122	SCV002821814	likely pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000680019	SCV000807458	uncertain significance	Progressive myoclonic epilepsy type 3	2017-09-01	flagged submission	clinical testing	Likely pathogenicity based on finding it once in our laboratory homozygous in a 2-year-old female with epilepsy, develomental delay, ataxia.