Submissions for variant NM_018100.4(EFHC1):c.779G>A (p.Arg260Gln)

gnomAD frequency: 0.00008  dbSNP: rs145754721

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766896	SCV000240931	uncertain significance	not provided	2015-10-21	criteria provided, single submitter	clinical testing	p.Arg260Gln (CGG>CAG): c.779 G>A in exon 5 of the EFHC1 gene (NM_018100.3). The R260Q variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The R260Q 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. However, this substitution occurs at a position that is not highly conserved across species within the second DM10 domain of the protein and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s).
Illumina Laboratory Services, Illumina	RCV000378920	SCV000464164	uncertain significance	Juvenile myoclonic epilepsy	2016-06-14	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000187346	SCV000613249	likely benign	not specified	2017-06-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765174	SCV001722081	benign	Absence seizure; Myoclonic epilepsy, juvenile, susceptibility to, 1	2022-02-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000187346	SCV005380672	likely benign	not specified	2024-08-12	criteria provided, single submitter	clinical testing	Variant summary: EFHC1 c.779G>A (p.Arg260Gln) results in a conservative amino acid change located in the DM10 domain (IPR006602) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 1613938 control chromosomes, predominantly at a frequency of 0.0018 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes (gnomAD v4.1.0). c.779G>A has been reported in the literature in at least an individual affected with Juvenile Myoclonic Epilepsy (example: Thounaojam_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Juvenile Myoclonic Epilepsy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34426522, 29750216). ClinVar contains an entry for this variant (Variation ID: 205389). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003907654	SCV004727238	likely benign	EFHC1-related disorder	2020-10-28	no assertion criteria provided	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).