ClinVar Genomic variation as it relates to human health
NM_153033.5(KCTD7):c.550C>T (p.Arg184Cys)
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.550C>T (p.Arg184Cys)
Variation ID: 36926 Accession: VCV000036926.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q11.21 7: 66638912 (GRCh38) [ NCBI UCSC ] 7: 66103899 (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 May 1, 2024 Feb 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_153033.5:c.550C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_694578.1:p.Arg184Cys missense NM_001167961.2:c.550C>T NP_001161433.1:p.Arg184Cys missense NC_000007.14:g.66638912C>T NC_000007.13:g.66103899C>T NG_028110.2:g.15032C>T LRG_835:g.15032C>T LRG_835t1:c.550C>T LRG_835p1:p.Arg184Cys Q96MP8:p.Arg184Cys - Protein change
- R184C
- Other names
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- Canonical SPDI
- NC_000007.14:66638911: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) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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 |
358 | 458 |
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
Help
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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Pathogenic (1) |
no assertion criteria provided
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Jul 13, 2012 | RCV000030608.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 19, 2018 | RCV000519234.2 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 16, 2023 | RCV000548914.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 12, 2021 | RCV001582502.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 28, 2024 | RCV002513270.3 |
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
Help
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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Pathogenic
(Aug 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Neuronal ceroid lipofuscinosis
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001821236.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Variant summary: KCTD7 c.550C>T (p.Arg184Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: KCTD7 c.550C>T (p.Arg184Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251302 control chromosomes. c.550C>T has been reported in the literature as a homozygous genotype in at-least three extensively genotyped (Whole Exome Sequencing, WES) individuals affected with features of Neuronal Ceroid-Lipofuscinosis (Batten Disease) and subsequently cited by others (example, Stropoli_2012, Monies_2019, Kohan_2015, Metz_2018). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect altered the localization pattern of KCTD7 and abrogated interaction with cullin-3, a ubiquitin-ligase component and known KCTD7 interactor (Staropoli_2012). Another publication reports altered potassium conductance and disrupts neuronal glutamine transporter (SAT2) activity (Moen_2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic/likely pathogenic citing overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Dec 05, 2019)
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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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Revvity Omics, Revvity
Accession: SCV002016784.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Likely pathogenic
(Jun 19, 2018)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000617302.2
First in ClinVar: Dec 19, 2017 Last updated: Apr 17, 2019 |
Comment:
The R184C variant in the KCTD7 gene has been identified in the homozygous state in 2 siblings with infantile-onset NCL; parental studies confirmed inheritance (Staropoli … (more)
The R184C variant in the KCTD7 gene has been identified in the homozygous state in 2 siblings with infantile-onset NCL; parental studies confirmed inheritance (Staropoli et al., 2012). Functional studies demonstrate R184C adversely affects the trafficking and/or solubility of KCTD7 (Staropoli et al., 2012). Moen et al. demonstrate that R184C abolishes K+ conductance and disrupts SAT2 activity which alters the depolorization of cells and impairs glutamine transport, respectively (Moen et al., 2016). The R184C variant is observed in 4/33578 (0.01%) alleles from individuals of Latino background (Lek et al., 2016). The R184C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. (less)
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Pathogenic
(Dec 16, 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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Invitae
Accession: SCV000646358.10
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 184 of the KCTD7 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 184 of the KCTD7 protein (p.Arg184Cys). This variant is present in population databases (rs387907246, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of infantile-onset neuronal ceroid lipofuscinosis in individual(s) and families (PMID: 22748208; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36926). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on KCTD7 function (PMID: 22748208, 27742667). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Feb 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003556778.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.550C>T (p.R184C) alteration is located in exon 4 (coding exon 4) of the KCTD7 gene. This alteration results from a C to T substitution … (more)
The c.550C>T (p.R184C) alteration is located in exon 4 (coding exon 4) of the KCTD7 gene. This alteration results from a C to T substitution at nucleotide position 550, causing the arginine (R) at amino acid position 184 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/251302) total alleles studied. The highest observed frequency was 0.012% (4/34570) of Latino alleles. This variant has been identified in the homozygous state in multiple individuals with features consistent with KCTD7-related progressive myoclonus epilepsy (Staropoli, 2012; Monies, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Pathogenic
(Jul 13, 2012)
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no assertion criteria provided
Method: literature only
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EPILEPSY, PROGRESSIVE MYOCLONIC, 3, WITH INTRACELLULAR INCLUSIONS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000053286.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016 |
Comment on evidence:
In 2 Mexican sibs with infantile onset of progressive myoclonic epilepsy (EPM3; 611726) and intracellular inclusions, consistent with a diagnosis of neuronal ceroid lipofuscinosis (designated … (more)
In 2 Mexican sibs with infantile onset of progressive myoclonic epilepsy (EPM3; 611726) and intracellular inclusions, consistent with a diagnosis of neuronal ceroid lipofuscinosis (designated CLN14), Staropoli et al. (2012) identified a homozygous 550C-T transition in exon 4 of the KCTD7 gene, resulting in an arg184-to-cys (R184C) substitution. The mutation was found by exome sequencing and confirmed by Sanger sequencing. Each unaffected parent was heterozygous for the mutation, which was not found in over 6,000 controls. In cerebellar cells, wildtype KCTD7 showed broad, punctate cytoplasmic localization and distinct signal at the plasma membrane, whereas mutant A184C showed more diffuse cytoplasmic localization, markedly diminished signaling at the plasma membrane, and prominent cytoplasmic aggregates. These results suggested that the mutation affects the trafficking and/or solubility of KCTD7. Studies in HEK293T cells showed that the R184C mutation abrogated the interaction with cullin-3 (CUL3; 603136), which Staropoli et al. (2012) suggested may lead to an accumulation of toxic intracellular proteins. (less)
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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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Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect. | Metz KA | Annals of neurology | 2018 | PMID: 30295347 |
Pathogenic variants in KCTD7 perturb neuronal K+ fluxes and glutamine transport. | Moen MN | Brain : a journal of neurology | 2016 | PMID: 27742667 |
The neuronal ceroid lipofuscinoses program: A translational research experience in Argentina. | Kohan R | Biochimica et biophysica acta | 2015 | PMID: 25976102 |
A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis to the ubiquitin-proteasome system. | Staropoli JF | American journal of human genetics | 2012 | PMID: 22748208 |
Text-mined citations for rs387907246 ...
HelpRecord last updated May 01, 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.