ClinVar Miner

Submissions for variant NM_004006.3(DMD):c.6571C>T (p.Arg2191Trp) (rs149322279)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000178576 SCV000230685 benign not specified 2015-04-13 criteria provided, single submitter clinical testing
GeneDx RCV000178576 SCV000235851 likely benign not specified 2017-12-08 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.
Invitae RCV001081226 SCV000560853 benign Duchenne muscular dystrophy 2019-12-31 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 Inc RCV000178576 SCV000613130 benign not specified 2016-09-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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 General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845549 SCV000987669 uncertain significance Familial dilated cardiomyopathy criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
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.

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