Submissions for variant NM_004006.3(DMD):c.*23_*35del

dbSNP: rs752332058

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000217670	SCV000235878	likely benign	not specified	2017-08-25	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217670	SCV000271679	uncertain significance	not specified	2015-06-24	criteria provided, single submitter	clinical testing	The p.Asp1223fs in DMD has not been previously reported in individuals with musc ular dystrophy or cardiomyopathy, but has been identified in 22/47909 European c hromosomes, including 6 hemizygotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). This variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning 28 amino acids upstre am of the C-terminus, leading to a termination codon 6 amino acids downstream. N onsense variants are generally predicted to cause absent protein; however when p resent in the last exon (as is the case for this variant), they are expected to result in a truncated protein. The established disease mechanism for DMD gene is loss of function and the role of other variants is less well understood. In add ition, this variant only affects the coding region on transcripts whose function al impact on skeletal and cardiac muscle is unclear (NM_004016.2, NM_004018.2, N M_004021.2; NM_004022.2, NM_004023.2). While the presence in hemizygous control individuals and lack of impact on coding region of the primary muscle dystrophi n isoform raises some doubt as to whether this variant can cause disease, the DM D gene has not been well sequenced in individuals with diagnoses other than Duch enne muscular dystrophy. Therefore the clinical significance of the p.Asp1223fs variant remains uncertain.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845490	SCV000987588	uncertain significance	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000999363	SCV001155940	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	DMD: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000217670	SCV001362910	benign	not specified	2019-09-27	criteria provided, single submitter	clinical testing	Variant summary: DMD c.*23_*35del13 is located in the untranslated mRNA region downstream of the termination codon. Though this variant also affects the coding region of other DMD transcripts (predictably disrupting their reading frame), the role of these affected dystrophin isoforms (e.g. Dp71 (NM_004016.2)) in disease currently is unclear. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00026 in 182672 control chromosomes. The observed variant frequency is approximately 23.33 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (1.1e-05), strongly suggesting that the variant is benign. c.*23_*35del13 has been reported in the literature in 3 individuals affected with Dystrophinopathies, however without strong evidence for causality (Nigro 1994, Spitali 2009, Santos 2014). In addition, in one of these cases the patient also carried a pathogenic DMD variant in cis (deletion of exons 46-50) that could explain his muscular phenotype, though authors noted that the loss of other DMD isoforms (caused by this variant) may have a cumulative effect thereby explaining the patients mental impairment (Santos 2014). On the other hand, another DMD patient carrying the variant of interest, had no mental impairment (Nigro 1994). 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. One laboratory classified the variant as benign/likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001517369	SCV001725852	benign	Duchenne muscular dystrophy	2023-04-24	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000999363	SCV001744749	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000217670	SCV001797434	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000999363	SCV001975089	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004539711	SCV004777779	likely benign	DMD-related disorder	2020-11-06	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).