Submissions for variant NM_004006.3(DMD):c.6571C>T (p.Arg2191Trp)

gnomAD frequency: 0.00020  dbSNP: rs149322279

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178576	SCV000230685	benign	not specified	2015-04-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000786293	SCV000235851	benign	not provided	2019-04-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 10573008, 7599634, 7849724, 11710958)
Invitae	RCV001081226	SCV000560853	benign	Duchenne muscular dystrophy	2024-01-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000178576	SCV000594379	likely benign	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000178576	SCV000613130	benign	not specified	2016-09-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000178576	SCV000711682	likely benign	not specified	2018-06-29	criteria provided, single submitter	clinical testing	The p.Arg2191Trp variant in DMD is classified as likely benign because it has be en identified in 0.03% (9/47899) of European chromosomes, including 14 hemizygot es, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org ; dbSNP rs149322279). It has also been reported in 3 individuals with clinical features of Duchenne Muscular Dystrophy, one of whom carried another pathogenic variant sufficient to cause disease (Nigro 1994, Kneppers 1995, Bennett 2001). ACMG/AMP Criteria applied: BS1, BP1, BP2.
Ambry Genetics	RCV000618624	SCV000737029	benign	Cardiovascular phenotype	2017-06-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845549	SCV000987669	uncertain significance	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000178576	SCV001361882	benign	not specified	2019-06-03	criteria provided, single submitter	clinical testing	Variant summary: DMD c.6571C>T (p.Arg2191Trp) results in a non-conservative amino acid change located in the Spectrin/alpha-actinin domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 182792 control chromosomes including 28 hemizygotes. The observed variant frequency is approximately 35-folds higher than 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. Co-occurrences with other pathogenic variant(s) have been reported (DMD c.2665C>T, p.Arg889X), providing supporting evidence for a benign role. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant six times as likely benign/benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000786293	SCV001473443	likely benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000786293	SCV004164723	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	DMD: BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV004539669	SCV004773360	likely benign	DMD-related disorder	2020-01-06	criteria provided, single submitter	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).
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786293	SCV000925054	likely benign	not provided	2017-11-08	no assertion criteria provided	provider interpretation	p.Arg2191Trp (c.6571C>T) in exon 45 of the DMD gene (NM_004006.2; ChrXg.31986499G>A) SCICD Classification: likely benign based on relatively high frequency in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: DMD encodes dystrophin, an integral skeletal muscle protein. Hemizygous pathogenic variants in DMD are the cause Duchenne and Becker muscular dystrophies. DMD is located on the X chromosome and thus males are most severely affected. The first signs are muscle weakness, and is often the major health issue for patients with DMD and BMD; however, males often pass away from heart failure and related complications. Importantly, carrier females can manifest symptoms associated with pathogenic variants in the DMD gene, most typically as dilated cardiomyopathy. About 20% of female carriers have EKG abnormalities. Female carriers can also have muscle weakness; however, this is rare. Loss of function variants in DMD are usually sufficient to cause disease. Case data (not including our patient): WEAK: this variant is present in at least 7 individuals referred for genetic testing; however, clinical phenotype is not clear. ClinVar: Invitae, GeneDx, EGL Genetic Diagnostics and the University of Chicago have submitted this variant to ClinVar, classified as either benign or likely benign. number of patients, evidence. Cases in the literature: Nigro et al (1994) reported this variant in one patient with Duchenne muscular dystropy. This variant is presumed de novo (not present in mother). Kneppers et al (1995) reported this variant in 1 of 70 patients with Duchenne/Becker Muscular dystrophy. They determined that this variant was not likely to be causative of DMD based on population data they had at the time. Bennett et al (2001) reported this variant in one patient with Duchenne muscular dystrophy. This patient had other variants that could have been causative of disease. Segregation data: none reported In silico data (missense variants only): Per the test report, "Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. " Conservation data: The arginine at codon 2191 is completely conserved across species. Neighboring amino acids are not completely conserved. Nearby pathogenic variants at this codon or neighboring codons: none Population data: Highest MAF in the Ashkenazi Jewish population: 0.26%%. The variant was reported online in 68 of 178,054 chromosomes in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 19 of 7,276 chromosomes of Ashkenazi Jewish descent (MAF=0.26%), 15 of 26,479 chromosomes of Latino descent, 25 of 79,602 chromosomes of European descent, 6 of 19,141 chromosomes of South Asian descent, 1 of 12,223 chromosomes of African descent and 2 of 4,039 chromosomes of "other" descent. This variant was present in 28 males. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000786293	SCV001742464	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000786293	SCV001968389	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826906	SCV002090311	likely benign	Becker muscular dystrophy; Duchenne muscular dystrophy; Cardiomyopathy; Dystrophin deficiency	2019-06-21	no assertion criteria provided	clinical testing