ClinVar Miner

Submissions for variant NM_153033.5(KCTD7):c.827A>G (p.Tyr276Cys)

gnomAD frequency: 0.00001  dbSNP: rs141191660
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001933893 SCV002205062 pathogenic Progressive myoclonic epilepsy type 3 2024-07-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 276 of the KCTD7 protein (p.Tyr276Cys). This variant is present in population databases (rs141191660, gnomAD 0.003%). This missense change has been observed in individual(s) with progressive myoclonic epilepsy (PMID: 25060828). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1427810). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects KCTD7 function (PMID: 27742667). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV003319493 SCV004023434 likely pathogenic not provided 2023-04-10 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect, including reduced CLN5 binding, absence of degradation or ubiquitination of CLN5 in HeLA cells, and severely impaired channel function in CHO cells (Moen et al., 2016; Wang et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24108619, 28162000, 30500434, 34469883, 30295347, 28761347, 25060828, 27742667, 35921411)
PreventionGenetics, part of Exact Sciences RCV004754810 SCV005351076 pathogenic KCTD7-related disorder 2024-07-24 no assertion criteria provided clinical testing The KCTD7 c.827A>G variant is predicted to result in the amino acid substitution p.Tyr276Cys. This variant has been reported in multiple patients with autosomal recessive KCTD7-related progressive myoclonic epilepsy, and segregation studies support its pathogenicity (Sawyer et al. 2014. PubMed ID: 24108619; Farhan et al. 2014. PubMed ID: 25060828; Metz et al. 2018. PubMed ID: 30295347; Wang et al. 2022. PubMed ID: 35921411). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.

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