chr7-66633410-C-T

Position:

• chr7-66633410-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_153033.5(KCTD7):​c.280C>T​(p.Arg94Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: KCTD7 NM_153033.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 4.49

Genes affected

KCTD7 (HGNC:21957): (potassium channel tetramerization domain containing 7) This gene encodes a member of the potassium channel tetramerization domain-containing protein family. Family members are identified on a structural basis and contain an amino-terminal domain similar to the T1 domain present in the voltage-gated potassium channel. Mutations in this gene have been associated with progressive myoclonic epilepsy-3. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2011]

ENSG00000284461 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain BTB (size 98) in uniprot entity KCTD7_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_153033.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-66633410-C-T is Pathogenic according to our data. Variant chr7-66633410-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD7	NM_153033.5	c.280C>T	p.Arg94Trp	missense_variant	2/4	ENST00000639828.2	NP_694578.1
KCTD7	NM_001167961.2	c.280C>T	p.Arg94Trp	missense_variant	2/5		NP_001161433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2	c.280C>T	p.Arg94Trp	missense_variant	2/4	2	NM_153033.5	ENSP00000492240.1
ENSG00000284461	ENST00000503687.2	n.144+4202C>T		intron_variant		2		ENSP00000421074.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152070 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251470 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461870 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152070 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74258

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive myoclonic epilepsy type 3 Pathogenic:5 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	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. -
Uncertain significance, flagged submission	clinical testing	Revvity Omics, Revvity	Mar 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Aug 22, 2017	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 19, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	Mar 13, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D;.;.;.;.;.
Eigen	Benign	-0.014
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.8	L;.;.;L;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.9	.;D;.;D;.;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	.;D;.;D;.;.
Sift4G	Uncertain	0.0030	.;D;.;D;.;.
Polyphen		0.13	B;.;.;.;.;.
Vest4		0.97, 0.96
MutPred		0.58		Loss of disorder (P = 0.0461);Loss of disorder (P = 0.0461);Loss of disorder (P = 0.0461);Loss of disorder (P = 0.0461);Loss of disorder (P = 0.0461);Loss of disorder (P = 0.0461);
MVP		0.85
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.70
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs387907260; hg19: chr7-66098397; COSMIC: COSV99299220;