Submissions for variant NM_000117.3(EMD):c.215A>T (p.Asp72Val)

gnomAD frequency: 0.00005  dbSNP: rs794729021

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726925	SCV000235912	uncertain significance	not provided	2015-04-30	criteria provided, single submitter	clinical testing	p.Asp72Val (GAT>GTT): c.215 A>T in exon 3 in the EMD gene (NM_000117.2). A variant of unknown significance has been identified in the EMD gene. The D72V variant has been reported in association with Emery -Driefuss muscular dystrophy in a gene specific database (BÂŽroud et al., 2000). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D72V 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 addition, in silico analysis predicts this variant is probably damaging to the protein structure/function. This substitution occurs at a position that is conserved in mammals. 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 EMD panel(s).
Eurofins Ntd Llc (ga)	RCV000726925	SCV000704203	uncertain significance	not provided	2016-12-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420800	SCV001623168	uncertain significance	not specified	2021-05-17	criteria provided, single submitter	clinical testing	Variant summary: EMD c.215A>T (p.Asp72Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183417 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.215A>T has been reported in the literature in at least an individual affected with Emery-Dreifuss Muscular Dystrophy and was also cited by others and found in UMD database (example: Essawy_2019, Puckelwartz_2011). These reports however, do not provide unequivocal conclusions about association of the variant with Emery-Dreifuss Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852357	SCV002145907	uncertain significance	X-linked Emery-Dreifuss muscular dystrophy	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 72 of the EMD protein (p.Asp72Val). This variant is present in population databases (rs794729021, gnomAD 0.005%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 12872622). ClinVar contains an entry for this variant (Variation ID: 201783). 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 with a negative predictive value of 80%. 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	RCV002415780	SCV002724647	uncertain significance	Cardiovascular phenotype	2023-09-12	criteria provided, single submitter	clinical testing	The p.D72V variant (also known as c.215A>T), located in coding exon 3 of the EMD gene, results from an A to T substitution at nucleotide position 215. The aspartic acid at codon 72 is replaced by valine, an amino acid with highly dissimilar properties. Based on data from gnomAD, the T allele has an overall frequency of 0.0009758% (2/204964) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.005369% (1/18625) of European (Finnish) alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001827990	SCV002084679	uncertain significance	Emery-Dreifuss muscular dystrophy	2020-11-02	no assertion criteria provided	clinical testing