Submissions for variant NM_004006.3(DMD):c.8038C>T (p.Arg2680Ter)

dbSNP: rs863225011

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000348940	SCV000255750	pathogenic	not provided	2018-09-20	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data.
Eurofins Ntd Llc (ga)	RCV000348940	SCV000345653	pathogenic	not provided	2016-09-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201174	SCV000550331	pathogenic	Duchenne muscular dystrophy	2022-08-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 217213). This premature translational stop signal has been observed in individuals with Duchenne muscular dystrophy (DMD) (PMID: 15351422, 16770791, 17041906, 18583217, 19835634, 19937601, 21396098, 25612904, 25636106). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2680*) in the DMD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DMD are known to be pathogenic (PMID: 16770791, 25007885).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192549	SCV001360768	pathogenic	Qualitative or quantitative defects of dystrophin	2019-06-17	criteria provided, single submitter	clinical testing	Variant summary: DMD c.8038C>T (p.Arg2680X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Large deletions downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 174421 control chromosomes. c.8038C>T has been reported in the literature in multiple individuals affected with Duchenne muscular dystrophy (eg. Tuffery-Giraud_2004, Flanigan_2011, Magri_2011, Connolly_2015, Ma_2018, Xu_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000348940	SCV002019385	pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000201174	SCV004048201	pathogenic	Duchenne muscular dystrophy		criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal at codon 2680 (p.Arg2680*) of the DMD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DMD are known to be pathogenic (Aartsma‐Rus et al). This variant has been reported in individuals affected with Duchenne muscular dystrophy (DMD) (Magri, Francesca, et al,Tuffery-Giraud, Sylvie, et al). This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change in DMD is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. For these reasons, this variant has been classified as pathogenic.