Submissions for variant NM_153033.5(KCTD7):c.456G>A (p.Val152=)

gnomAD frequency: 0.00001  dbSNP: rs796052686

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188011	SCV000241614	uncertain significance	not provided	2017-08-24	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the KCTD7 gene. The c.456 G>A variant hasnot been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). Several in silico splice prediction models predict that c.456 G>A strengthens a cryptic splice donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Undiagnosed Diseases Network, NIH	RCV000545317	SCV000746647	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	RCV000545317	SCV001611476	pathogenic	Progressive myoclonic epilepsy type 3	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change affects codon 152 of the KCTD7 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the KCTD7 protein. This variant is present in population databases (rs796052686, gnomAD 0.009%). This variant has been observed in individual(s) with clinical features of progressive myoclonic epilepsy (PMID: 31160820, 33970744; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 206004). Studies have shown that this variant alters KCTD7 gene expression (PMID: 31160820, 33970744). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.