rs201296399
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_153033.5(KCTD7):āc.190A>Gā(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).
Frequency
Consequence
NM_153033.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCTD7 | NM_153033.5 | c.190A>G | p.Thr64Ala | missense_variant | Exon 2 of 4 | ENST00000639828.2 | NP_694578.1 | |
KCTD7 | NM_001167961.2 | c.190A>G | p.Thr64Ala | missense_variant | Exon 2 of 5 | NP_001161433.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCTD7 | ENST00000639828.2 | c.190A>G | p.Thr64Ala | missense_variant | Exon 2 of 4 | 2 | NM_153033.5 | ENSP00000492240.1 | ||
ENSG00000284461 | ENST00000503687.2 | n.144+4112A>G | intron_variant | Intron 1 of 12 | 2 | ENSP00000421074.1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152030Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251300Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135824
GnomAD4 exome AF: 0.000110 AC: 161AN: 1461674Hom.: 0 Cov.: 32 AF XY: 0.000111 AC XY: 81AN XY: 727146
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152030Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74264
ClinVar
Submissions by phenotype
Progressive myoclonic epilepsy type 3 Pathogenic:2Uncertain:1
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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:1Uncertain:2
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Published functional studies suggest this variant affects subcellular localization and alters protein function (PMID: 30295347); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27742667, 25533962, 26795593, 22748208, 29056246, 25060828, 30825425, 38231304, 34395220, 30295347, 32412666) -
Inborn genetic diseases Pathogenic:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at