Submissions for variant NM_004006.3(DMD):c.9100C>T (p.Arg3034Ter)

dbSNP: rs1569530432

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690515	SCV000818202	pathogenic	Duchenne muscular dystrophy	2023-08-06	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 569802). This premature translational stop signal has been observed in individuals with Duchenne muscular dystrophy (PMID: 15723292, 21515508, 27593222). This sequence change creates a premature translational stop signal (p.Arg3034*) 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).
Athena Diagnostics	RCV000711471	SCV000841839	pathogenic	not provided	2018-05-16	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000711471	SCV000854979	pathogenic	not provided	2018-01-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293608	SCV001482226	pathogenic	Qualitative or quantitative defects of dystrophin	2021-02-03	criteria provided, single submitter	clinical testing	Variant summary: DMD c.9100C>T (p.Arg3034X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 179879 control chromosomes. c.9100C>T has been reported in the literature in individuals affected with Dystrophinopathies (e.g. Dent_2005, Juan-Mateu_2015, Cho_2017, Wang_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000711471	SCV001769876	pathogenic	not provided	2020-02-25	criteria provided, single submitter	clinical testing	Reported previously in association with dystrophinopathy in several unrelated males (Dent et al., 2005; Flanigan et al., 2009; Cho et al, 2017); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); 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: 19937601, 21396098, 25972034, 27593222, 25525159, 30833962, 15723292)
Revvity Omics, Revvity	RCV000711471	SCV002018575	pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing
3billion	RCV000690515	SCV002521066	pathogenic	Duchenne muscular dystrophy	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000569802 / PMID: 15723292). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV003303125	SCV003990565	pathogenic	Cardiovascular phenotype	2023-04-17	criteria provided, single submitter	clinical testing	The p.R3034* pathogenic mutation (also known as c.9100C>T), located in coding exon 61 of the DMD gene, results from a C to T substitution at nucleotide position 9100. This changes the amino acid from an arginine to a stop codon within coding exon 61. This variant has been detected in multiple affected individuals from dystrophinopathy cohorts, including males with Duchenne muscular dystrophy and females with milder presentations (Dent KM et al. Am J Med Genet A, 2005 Apr;134:295-8; Flanigan KM et al. Hum Mutat, 2009 Dec;30:1657-66; Soltanzadeh P et al. Neuromuscul Disord, 2010 Aug;20:499-504; Magri F et al. BMC Med Genet, 2011 Mar;12:37; Mah JK et al. Can J Neurol Sci, 2011 May;38:465-74; Forbes SC et al. Neuromuscul Disord, 2012 Oct;22 Suppl 2:S111-21; Guo R et al. J Hum Genet, 2015 Aug;60:435-42; Kim MJ et al. J Mol Diagn, 2016 Mar;18:253-9; Ebrahimi-Fakhari D et al. Front Pediatr, 2018 Oct;6:316; Kohli S et al. Indian J Pediatr, 2020 Jul;87:495-504; Brogna C et al. Neuromuscul Disord, 2021 Jun;31:479-488). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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	RCV000690515	SCV004013933	pathogenic	Duchenne muscular dystrophy	2023-06-12	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5