NM_153033.5(KCTD7):c.280C>T (p.Arg94Trp) AND Progressive myoclonic epilepsy type 3

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Nov 24, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000030687.20

Allele description

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

Gene:

KCTD7:potassium channel tetramerization domain containing 7 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q11.21

Genomic location:

Preferred name:

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

HGVS:

NC_000007.14:g.66633410C>T
NG_028110.2:g.9530C>T
NM_001167961.2:c.280C>T
NM_153033.5:c.280C>TMANE SELECT
NP_001161433.1:p.Arg94Trp
NP_694578.1:p.Arg94Trp
LRG_835t1:c.280C>T
LRG_835:g.9530C>T
LRG_835p1:p.Arg94Trp
NC_000007.13:g.66098397C>T
NM_153033.2:c.280C>T
NM_153033.4:c.280C>T
Q96MP8:p.Arg94Trp
p.R94W

Protein change:

R94W; ARG94TRP

Links:

UniProtKB: Q96MP8#VAR_068776; OMIM: 611725.0003; dbSNP: rs387907260

NCBI 1000 Genomes Browser:

rs387907260

Molecular consequence:

NM_001167961.2:c.280C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_153033.5:c.280C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Progressive myoclonic epilepsy type 3
Synonyms:: EPILEPSY, PROGRESSIVE MYOCLONIC, 3, WITH OR WITHOUT INTRACELLULAR INCLUSIONS; CEROID LIPOFUSCINOSIS, NEURONAL, 14; EPILEPSY, PROGRESSIVE MYOCLONIC, 3, WITHOUT INTRACELLULAR INCLUSIONS
Identifiers:: MONDO: MONDO:0012721; MedGen: C2673257; Orphanet: 263516; OMIM: 611726

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IRS4 Irs4p [Saccharomyces cerevisiae S288C]
IRS4 Irs4p [Saccharomyces cerevisiae S288C]
Gene ID:853889

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000053348	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2012)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000746646	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 22, 2017)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001484913	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 24, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22606975, 22693283, 34866617, 27742667, 28492532
SCV001573224	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 13, 2020)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003812043	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 29, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	3	1	not provided	3	yes	clinical testing
Mexican	paternal	yes	2	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel mutation in potassium channel related gene KCTD7 and progressive myoclonic epilepsy.

Krabichler B, Rostasy K, Baumann M, Karall D, Scholl-Bürgi S, Schwarzer C, Gautsch K, Spreiz A, Kotzot D, Zschocke J, Fauth C, Haberlandt E.

Ann Hum Genet. 2012 Jul;76(4):326-31. doi: 10.1111/j.1469-1809.2012.00710.x. Epub 2012 May 21.

PubMed [citation]

PMID:: 22606975

Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy gene.

Kousi M, Anttila V, Schulz A, Calafato S, Jakkula E, Riesch E, Myllykangas L, Kalimo H, Topçu M, Gökben S, Alehan F, Lemke JR, Alber M, Palotie A, Kopra O, Lehesjoki AE.

J Med Genet. 2012 Jun;49(6):391-9. doi: 10.1136/jmedgenet-2012-100859.

PubMed [citation]

PMID:: 22693283
PMCID:: PMC3773914

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000053348.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a Turkish boy with progressive myoclonic epilepsy-3 (EPM3; 611726), Kousi et al. (2012) identified a homozygous 280C-T transition in exon 2 of the KCTD7 gene, resulting in an arg94-to-trp (R94W) substitution. The mutation was not found in 150 Turkish control chromosomes.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV000746646.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Mexican	2	not provided	not provided	clinical testing (GTR000553916.1)	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	not provided	not provided	not provided	(GTR000553916.1)	2	not provided	1	not provided

From Invitae, SCV001484913.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV001573224.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	yes	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	3	not provided	discovery		3	not provided	1	not provided

From Revvity Omics, Revvity, SCV003812043.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2024

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