ClinVar Miner

Submissions for variant NM_153033.4(KCTD7):c.550C>T (p.Arg184Cys) (rs387907246)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519234 SCV000617302 likely pathogenic not provided 2018-06-19 criteria provided, single submitter clinical testing 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.
Invitae RCV000548914 SCV000646358 pathogenic Epilepsy, progressive myoclonic 3 2019-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 184 of the KCTD7 protein (p.Arg184Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs387907246, ExAC 0.02%). This variant has been observed to segregate with clinical features of infantile-onset neuronal ceroid lipofuscinosis in individual(s) and families (PMID: 22748208, Invitae). ClinVar contains an entry for this variant (Variation ID: 36926). Experimental studies of this missense change report conflicting data for plasma membrane levels of KCTD7 protein (PMID: 22748208, 27742667). Electrophysiology data shows abolished K+ conductance, impaired SAT2 (Slc38a2) activity, and abrogated the interaction with Cullin-3 protein, however the clinical relevance of these observations is unclear (PMID: 2274208, 27742667). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000030608 SCV000053286 pathogenic Epilepsy, progressive myoclonic, 3, with intracellular inclusions 2012-07-13 no assertion criteria provided literature only

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