Submissions for variant NM_153033.5(KCTD7):c.280C>T (p.Arg94Trp)

gnomAD frequency: 0.00001  dbSNP: rs387907260

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000030687	SCV000746646	likely pathogenic	Progressive myoclonic epilepsy type 3	2017-08-22	criteria provided, single submitter	clinical testing	Heterozygous c.280C>T (p.R94W) likely pathogenic variant and c.456G>A (p.V152V) variant of unknown clinical significance in the KCTD7 gene were detected by exome sequencing and confirmed by Sanger sequencing this individual and her similarly affected younger brother. The c.280C>T (p.R94W) likely pathogenic variant has been previously reported in the homozygous state in two apparently unrelated Turkish patients [PMID 22693283, 22606975]. The potential pathogenicity of the variant is also supported by a recent functional study [PMID 27742667]. The c.456G>A (p.V152V) variant was predicted to affect splicing by in silico modeling. This effect on splicing was confirmed by RNA sequencing which showed evidence of a novel splice donor site that prematurely terminates exon 3 of KCTD7 in patient samples. Splicing effect was also confirmed by Sanger sequencing of amplified cDNA corresponding to KCTD7 exons 2-4 which showed two discrete bands in patients compared to one band in unrelated controls [Zastrow et al., ASHG 2017]. Whole exome sequencing analysis and Sanger analysis showed that the father is heterozygous for c.280C>T (p.R94W) and the mother is heterozygous for c.456G>A (p.V152V), indicating the two variants are in trans in this individual and her brother.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000030687	SCV001484913	likely pathogenic	Progressive myoclonic epilepsy type 3	2024-02-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 94 of the KCTD7 protein (p.Arg94Trp). This variant is present in population databases (rs387907260, gnomAD 0.004%). This missense change has been observed in individuals with progressive myoclonic epilepsy (PMID: 22606975, 22693283, 34866617). ClinVar contains an entry for this variant (Variation ID: 37010). 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) performed at Invitae indicates that this missense variant is not expected to disrupt KCTD7 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects KCTD7 function (PMID: 27742667). 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.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000030687	SCV001573224	likely pathogenic	Progressive myoclonic epilepsy type 3	2020-03-13	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000030687	SCV005442205	likely pathogenic	Progressive myoclonic epilepsy type 3	2024-12-19	criteria provided, single submitter	clinical testing
OMIM	RCV000030687	SCV000053348	pathogenic	Progressive myoclonic epilepsy type 3	2012-06-01	no assertion criteria provided	literature only
Revvity Omics, Revvity	RCV000030687	SCV003812043	uncertain significance	Progressive myoclonic epilepsy type 3	2021-03-29	flagged submission	clinical testing