ClinVar Miner

Submissions for variant NM_153033.5(KCTD7):c.190A>G (p.Thr64Ala)

gnomAD frequency: 0.00005  dbSNP: rs201296399
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000712134 SCV000227565 uncertain significance not provided 2016-11-07 criteria provided, single submitter clinical testing
GeneDx RCV000712134 SCV000241621 pathogenic not provided 2024-02-20 criteria provided, single submitter clinical testing 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)
Ambry Genetics RCV000624660 SCV000740750 likely pathogenic Inborn genetic diseases 2018-09-06 criteria provided, single submitter clinical testing 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000645671 SCV000767422 pathogenic Progressive myoclonic epilepsy type 3 2024-08-14 criteria provided, single submitter clinical testing 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.
Athena Diagnostics RCV000712134 SCV000842556 uncertain significance not provided 2018-03-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001797663 SCV002041836 uncertain significance not specified 2021-11-03 criteria provided, single submitter clinical testing 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.
Revvity Omics, Revvity RCV000645671 SCV003812045 uncertain significance Progressive myoclonic epilepsy type 3 2019-05-30 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000645671 SCV005667435 likely pathogenic Progressive myoclonic epilepsy type 3 2024-04-23 criteria provided, single submitter clinical testing

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