Submissions for variant NM_000117.3(EMD):c.454C>T (p.Arg152Cys)

gnomAD frequency: 0.00006  dbSNP: rs376456050

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179255	SCV000231475	uncertain significance	not provided	2017-10-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000616618	SCV000820492	likely benign	X-linked Emery-Dreifuss muscular dystrophy	2024-11-27	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000179255	SCV001143862	likely benign	not provided	2019-03-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298506	SCV002598550	uncertain significance	not specified	2022-09-26	criteria provided, single submitter	clinical testing	Variant summary: EMD c.454C>T (p.Arg152Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico toos predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 183082 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in EMD causing Emery-Dreifuss Muscular Dystrophy (6e-05 vs 0.001), allowing no conclusion about variant significance. c.454C>T has been reported in the literature in individuals affected with cardiac myopathies, however, three publications classified the variant as VUS (example: Mook_2013, Paendonck-Zwarts_2014 and Verdonschot_2020). These reports 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS(n=1) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV003491930	SCV003833447	uncertain significance	Emery-Dreifuss muscular dystrophy 1, X-linked	2019-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV005328223	SCV005991189	uncertain significance	Cardiovascular phenotype	2025-01-25	criteria provided, single submitter	clinical testing	The p.R152C variant (also known as c.454C>T), located in coding exon 6 of the EMD gene, results from a C to T substitution at nucleotide position 454. The arginine at codon 152 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in individual(s) with features consistent with dilated and hypertrophic cardiomyopathy (van Spaendonck-Zwarts KY et al. Eur J Heart Fail, 2013 Jun;15:628-36; Mook OR et al. J Med Genet, 2013 Sep;50:614-26; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). Based on data from gnomAD, the T allele has an overall frequency of 0.006% (11/183082) total alleles studied, with 3 hemizygote(s) observed. The highest observed frequency was 0.011% (9/81667) of European (non-Finnish) alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000616618	SCV000734765	uncertain significance	X-linked Emery-Dreifuss muscular dystrophy		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000179255	SCV001923533	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000179255	SCV001928924	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000179255	SCV001952098	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000179255	SCV001973556	uncertain significance	not provided		no assertion criteria provided	clinical testing