ClinVar Genomic variation as it relates to human health
NM_153033.5(KCTD7):c.280C>T (p.Arg94Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_153033.5(KCTD7):c.280C>T (p.Arg94Trp)
Variation ID: 37010 Accession: VCV000037010.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q11.21 7: 66633410 (GRCh38) [ NCBI UCSC ] 7: 66098397 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 23, 2016 Feb 14, 2024 Nov 24, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_153033.5:c.280C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_694578.1:p.Arg94Trp missense NM_001167961.2:c.280C>T NP_001161433.1:p.Arg94Trp missense NM_153033.4:c.280C>T NC_000007.14:g.66633410C>T NC_000007.13:g.66098397C>T NG_028110.2:g.9530C>T LRG_835:g.9530C>T LRG_835t1:c.280C>T LRG_835p1:p.Arg94Trp Q96MP8:p.Arg94Trp - Protein change
- R94W
- Other names
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- Canonical SPDI
- NC_000007.14:66633409:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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KCTD7 | - | - |
GRCh38 GRCh37 |
360 | 460 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Nov 24, 2023 | RCV000030687.21 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Aug 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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Progressive myoclonic epilepsy type 3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000746646.1 First in ClinVar: Oct 23, 2016 Last updated: Oct 23, 2016 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 2
Clinical Features:
Synophrys (present) , Small hand (present) , Short stature (present) , Short nose (present) , Short foot (present) , Seizures (present) , Nevus flammeus of … (more)
Synophrys (present) , Small hand (present) , Short stature (present) , Short nose (present) , Short foot (present) , Seizures (present) , Nevus flammeus of the forehead (present) , Nevus flammeus nuchae (present) , Loss of speech (present) , Loss of ability to walk (present) , High palate (present) , Hallux valgus (present) , Generalized myoclonic seizures (present) , Gastrostomy tube feeding in infancy (present) , Flexion contracture (present) , Dysphagia (present) , Downslanted palpebral fissures (present) , Developmental regression (present) , Deep palmar crease (present) , Decreased palmar creases (present) , Anteverted nares (present) (less)
Age: 6-14 years
Sex: female
Ethnicity/Population group: Mexican
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2017-08-22
Testing laboratory interpretation: Likely pathogenic
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Likely pathogenic
(Mar 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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Progressive myoclonic epilepsy type 3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV001573224.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Number of individuals with the variant: 3
Family history: yes
Sex: female
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Likely pathogenic
(Nov 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Progressive myoclonic epilepsy type 3
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001484913.4
First in ClinVar: Mar 07, 2021 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jun 01, 2012)
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no assertion criteria provided
Method: literature only
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EPILEPSY, PROGRESSIVE MYOCLONIC, 3, WITHOUT INTRACELLULAR INCLUSIONS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000053348.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016 |
Comment on evidence:
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 … (more)
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. (less)
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Uncertain significance
(Mar 29, 2021)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Progressive myoclonic epilepsy type 3
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003812043.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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KCTD7-related progressive myoclonic epilepsy: report of three Indian families and review of literature. | Narayanan DL | Clinical dysmorphology | 2022 | PMID: 34866617 |
Pathogenic variants in KCTD7 perturb neuronal K+ fluxes and glutamine transport. | Moen MN | Brain : a journal of neurology | 2016 | PMID: 27742667 |
Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy gene. | Kousi M | Journal of medical genetics | 2012 | PMID: 22693283 |
Novel mutation in potassium channel related gene KCTD7 and progressive myoclonic epilepsy. | Krabichler B | Annals of human genetics | 2012 | PMID: 22606975 |
Text-mined citations for rs387907260 ...
HelpRecord last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.