rs201296399

Positions:

• chr7-66633320-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_153033.5(KCTD7):​c.190A>G​(p.Thr64Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T64T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: KCTD7 NM_153033.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 8.65

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain BTB (size 98) in uniprot entity KCTD7_HUMAN there are 16 pathogenic changes around while only 2 benign (89%) in NM_153033.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• PP5: Variant 7-66633320-A-G is Pathogenic according to our data. Variant chr7-66633320-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195417.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Likely_pathogenic=2, Pathogenic=1}. Variant chr7-66633320-A-G is described in Lovd as [Likely_pathogenic]. Variant chr7-66633320-A-G is described in Lovd as [Pathogenic]. Variant chr7-66633320-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCTD7	NM_153033.5	c.190A>G	p.Thr64Ala	missense_variant	2/4	ENST00000639828.2
KCTD7	NM_001167961.2	c.190A>G	p.Thr64Ala	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCTD7	ENST00000639828.2	c.190A>G	p.Thr64Ala	missense_variant	2/4	2	NM_153033.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152030 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251300 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135824

Gnomad AFR exome AF: 0.000123

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: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1461674 Hom.: 0 Cov.: 32 AF XY: 0.000111 AC XY: 81 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000139

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152030 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74264

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000251 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 14, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2023	Published functional studies suggest this variant affects subcellular localization and alters protein function (Metz et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27742667, 25533962, 26795593, 22748208, 29056246, 25060828, 30295347, 30825425, 32412666, 34395220) -

Progressive myoclonic epilepsy type 3 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 30, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 64 of the KCTD7 protein (p.Thr64Ala). This variant is present in population databases (rs201296399, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of progressive myoclonic epilepsy (PMID: 26795593, 29056246, 30295347, 32412666). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 195417). 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: 30295347). 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. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2018

The p.T64A variant (also known as c.190A>G), located in coding exon 2 of the KCTD7 gene, results from an A to G substitution at nucleotide position 190. The threonine at codon 64 is replaced by alanine, an amino acid with similar properties. This alteration was confirmed in trans with a likely pathogenic alteration in an individual with seizures and developmental regression (Helbig KL et al. Genet. Med., 2016 Sep;18:898-905). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 03, 2021

Variant summary: KCTD7 c.190A>G (p.Thr64Ala) results in a non-conservative amino acid change located in the BTB/POZ domain (IPR000210) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251300 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in KCTD7 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (5.6e-05 vs 0.00035), allowing no conclusion about variant significance. c.190A>G has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis and Progressive Myoclonus Epilepsy (DDDS_2014, Helbig_2016, Butler_2017, Metz_2018, Kozina_2020). These data indicate that the variant may be associated with disease. At least one functional study reports experimental evidence evaluating an impact on protein function and this variant affects protein function, including CUL3 interaction and altered subcellular localization (Metz_2018). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.3	M;.;.;M;.;.
MutationTaster	Benign	0.77	N
PrimateAI	Uncertain	0.74	T
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.98, 0.98
MVP		0.85
ClinPred		0.83	D
GERP RS		4.8
Varity_R		0.77
gMVP		0.85

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: rs201296399; hg19: chr7-66098307;