Submissions for variant NM_018100.4(EFHC1):c.1114C>T (p.Arg372Trp)

gnomAD frequency: 0.00003  dbSNP: rs371151471

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766897	SCV000240945	uncertain significance	not provided	2016-01-05	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the EFHC1 gene. The R372W variant has been reported previously in association with juvenile myoclonic epilepsy; however, additional information was not provided (Praveen K et al., 2013). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports R372W was observed in 10/978 (1%) alleles from individuals of South Asian background, indicating it may be a rare (benign) variant in this population. This substitution occurs at a position that is not conserved. However, the R372W 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 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 variant or a rare benign variant.
Genetic Services Laboratory, University of Chicago	RCV000187360	SCV000247257	uncertain significance	not specified	2014-08-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765183	SCV000290436	benign	Absence seizure; Myoclonic epilepsy, juvenile, susceptibility to, 1	2023-02-10	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000226361	SCV000898665	uncertain significance	Absence seizure; Juvenile myoclonic epilepsy	2018-07-09	criteria provided, single submitter	clinical testing	EFHC1 NM_018100.3 exon 6 p.Arg372Trp (c.1114C>T): This variant has been reported in the literature in several individuals with Juvenile Myoclonic Epilepsy (JME) (Raju 2017 PMID:28370826). However, this variant is present in 0.9% (304/30778) of South Asian alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs371151471). This variant is present in ClinVar (Variation ID:205403). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224206	SCV003919913	uncertain significance	Myoclonic epilepsy, juvenile, susceptibility to, 1; Epilepsy, juvenile absence, susceptibility to, 1	2021-03-30	criteria provided, single submitter	clinical testing	EFHC1 NM_018100.3 exon 6 p.Arg372Trp (c.1114C>T): This variant has been reported in the literature in several individuals with Juvenile Myoclonic Epilepsy (JME) (Raju 2017 PMID:28370826). However, this variant is present in 0.9% (304/30778) of South Asian alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs371151471). This variant is present in ClinVar (Variation ID:205403). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Revvity Omics, Revvity	RCV000766897	SCV004234680	uncertain significance	not provided	2023-11-20	criteria provided, single submitter	clinical testing