Submissions for variant NM_000117.3(EMD):c.608G>A (p.Arg203His)

gnomAD frequency: 0.00004  dbSNP: rs144842093

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183444	SCV000235904	uncertain significance	not provided	2017-01-12	criteria provided, single submitter	clinical testing	The R203H variant of uncertain significance in the EMD gene was reported in a review paper in an individual who developed symptoms of EDMD at 10 years of age; however, a citation for the primary reference about this individual was not provided (Funakoshi et al., 1999). This individual reportedly had a history of muscle weakness and complete atrio-ventricular (AV) conduction block (Funakoshi et al., 1999). Although this variant has not been observed at a significant frequency in large population cohorts, it has been reported as hemizygous in several individuals from these cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server; Exome Aggregation Consortium). The R203H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. 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 pathogenic or benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000551176	SCV000636285	uncertain significance	X-linked Emery-Dreifuss muscular dystrophy	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 203 of the EMD protein (p.Arg203His). This variant is present in population databases (rs144842093, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of EMD-related conditions (PMID: 29349559). ClinVar contains an entry for this variant (Variation ID: 201775). 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 not expected to disrupt EMD protein function. 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.
Ambry Genetics	RCV004020214	SCV005032372	uncertain significance	Cardiovascular phenotype	2023-11-17	criteria provided, single submitter	clinical testing	The p.R203H variant (also known as c.608G>A), located in coding exon 6 of the EMD gene, results from a G to A substitution at nucleotide position 608. The arginine at codon 203 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in an infant with right bundle branch block and left ventricular noncompaction, who also carried alterations in other cardiac-related genes (Yokoyama R et al. Heart Vessels, 2018 Jul;33:802-819). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (8/204893) total alleles studied, with 2 hemizygote(s) observed. The highest observed frequency was <0.01% (6/14848) of East Asian alleles. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001271618	SCV001452894	uncertain significance	Emery-Dreifuss muscular dystrophy	2020-09-16	no assertion criteria provided	clinical testing