ClinVar Miner

Submissions for variant NM_018100.4(EFHC1):c.1306C>T (p.Arg436Cys)

gnomAD frequency: 0.00006  dbSNP: rs377286138
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000724108 SCV000232760 uncertain significance not provided 2014-10-03 criteria provided, single submitter clinical testing
GeneDx RCV000724108 SCV000240951 uncertain significance not provided 2013-09-17 criteria provided, single submitter clinical testing p.Arg436Cys (R436C) CGC>TGC: c.1306 C>T in exon 8 of the EFHC1 gene (NM_018100.3). The Arg436Cys missense change in the EFHC1 gene has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This variant is a non-conservative amino acid substitution of a positively charged Arginine residue with an uncharged Cysteine residue, and the addition of a Cysteine may affect disulfide bonding and the secondary structure of the protein. The variant alters a conserved position in the DM10-3 domain of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, based on the currently available information, it is unclear whether Arg436Cys is a disease-causing mutation or a rare benign variant.Therefore, based on the currently available information, it is unclear whether R436C is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV003765104 SCV000552800 uncertain significance Absence seizure; Myoclonic epilepsy, juvenile, susceptibility to, 1 2024-02-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 436 of the EFHC1 protein (p.Arg436Cys). This variant is present in population databases (rs377286138, gnomAD 0.03%). This missense change has been observed in individual(s) with myoclonic epilepsy (PMID: 28370826; Invitae). ClinVar contains an entry for this variant (Variation ID: 198888). 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 expected to disrupt EFHC1 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on EFHC1 function (PMID: 28370826). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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