Submissions for variant NM_018100.4(EFHC1):c.661C>T (p.Arg221Cys)

gnomAD frequency: 0.00019  dbSNP: rs139197513

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766895	SCV000240924	uncertain significance	not provided	2015-10-19	criteria provided, single submitter	clinical testing	p.Arg221Cys (CGT>TGT): c.661 C>T in exon 4 of the EFHC1 gene (NM_018100.3). The R221C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. A different amino acid substitution at the same position, R221H, co-segregated with juvenile myoclonic epilepsy (JME) in two families, both of whom also had the P77T variant on the same chromosome (Suzuki et al., 2004). Functional studies suggest R221H impairs apoptosis and alters calcium currents, suggesting this residue is important for normal protein function (Suzuki et al., 2004). However, this position is not well conserved through evolution. The R221C amino acid substitution is non-conservative, as a positively charged Arginine residue is replaced by an uncharged Cysteine residue, and the gain of a Cysteine residue could affect disulfide bond formation in the protein. Multiple in silico algorithms predict R221C may be damaging to protein structure/function. Therefore, based on the currently available information, it is unclear whether R221C is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae	RCV003765171	SCV000290438	benign	Absence seizure; Myoclonic epilepsy, juvenile, susceptibility to, 1	2023-07-17	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000187340	SCV000332930	likely benign	not specified	2015-07-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766895	SCV004163607	benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	EFHC1: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003947569	SCV004771098	likely benign	EFHC1-related condition	2021-03-19	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).