Submissions for variant NM_004006.3(DMD):c.4729C>T (p.Arg1577Ter)

dbSNP: rs863224999

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000255348	SCV000255730	pathogenic	not provided	2020-07-28	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
GeneDx	RCV000255348	SCV000322284	pathogenic	not provided	2023-05-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Based on the understanding of this genetic alteration, it may be amenable to nonsense read-through therapy that is currently available or in clinical trial; This variant is associated with the following publications: (PMID: 19783145, 21515508, 21972111, 28503591, 12233050, 20485447, 19937601, 25525159, 23453023, 18652600, 26110187, 28332368, 28318817, 31412794, 32559196, 34297739, 34925456)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201158	SCV000550291	pathogenic	Duchenne muscular dystrophy	2024-05-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1577*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Duchenne muscular dystrophy (PMID: 18652600, 19783145, 20485447, 21515508, 23453023). ClinVar contains an entry for this variant (Variation ID: 217199). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000255348	SCV000700805	pathogenic	not provided	2017-01-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193218	SCV001361929	pathogenic	Qualitative or quantitative defects of dystrophin	2019-10-17	criteria provided, single submitter	clinical testing	Variant summary: DMD c.4729C>T (p.Arg1577X) 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. The variant was absent in 182057 control chromosomes (gnomAD). c.4729C>T has been reported in the literature in multiple individuals affected with Dystrophinopathies. Most of these individuals were affected with DMD (Duchenne Muscular Dystrophy)(e.g. Esterhuizen_2014, Flanigan_2011, Takeshima_2010) .These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000255348	SCV002018704	pathogenic	not provided	2022-11-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336547	SCV002639250	pathogenic	Cardiovascular phenotype	2020-04-22	criteria provided, single submitter	clinical testing	The p.R1577* pathogenic mutation (also known as c.4729C>T), located in coding exon 34 of the DMD gene, results from a C to T substitution at nucleotide position 4729. This changes the amino acid from an arginine to a stop codon within coding exon 34. This alteration has been reported in multiple individuals with Duchenne muscular dystrophy (DMD) (Takeshima Y et al. J. Hum. Genet., 2010 Jun;55:379-88; Sedlácková J et al. Neuromuscul. Disord., 2009 Nov;19:749-53; Yang J et al. BMC Med. Genet., 2013 Mar;14:29; Mah JK et al. Can J Neurol Sci, 2011 May;38:465-74; Suh MR et al. Yonsei Med. J., 2017 May;58:613-618; Vieitez I et al. Neurologia Mar;32:377-385; Kong X et al. BMC Med. Genet., 2019 08;20:139; Flanigan KM et al. Hum. Mutat., 2009 Dec;30:1657-66). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000201158	SCV002769603	pathogenic	Duchenne muscular dystrophy	2022-12-16	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Genomic Medicine Lab, University of California San Francisco	RCV003997034	SCV004847115	pathogenic	Dilated cardiomyopathy 3B	2023-04-06	criteria provided, single submitter	clinical testing