Submissions for variant NM_004006.3(DMD):c.3432+2036A>G

dbSNP: rs182575709

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537797	SCV000625893	pathogenic	Duchenne muscular dystrophy	2024-06-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 25 of the DMD gene. It does not directly change the encoded amino acid sequence of the DMD protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has been observed in individuals with features of Becker muscular dystrophy (PMID: 12754707, 16770791). This variant is also known as IVS25+2036A>G. ClinVar contains an entry for this variant (Variation ID: 455893). Studies have shown that this variant results in inclusion of a pseudoexon and introduces a premature termination codon (PMID: 12754707). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000537797	SCV001445931	likely pathogenic	Duchenne muscular dystrophy	2020-06-03	criteria provided, single submitter	curation	The hemizygous c.3432+2036A>G variant in DMD was identified by our study in 1 individual with muscular dystrophy. The variant has been reported in 3 individuals of with Becker muscular dystrophy (PMID: 12754707; LOVD, PMID: 16770791), and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 455893) as likely pathogenic by Invitae. In vitro functional studies provide some evidence that the c.3432+2036A>G variant may impact protein function (PMID: 12754707). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for Becker muscular dystrophy. ACMG/AMP Criteria applied: PM2, PP3, PS3_supporting, PS4_moderate (Richards 2015).
GeneDx	RCV001539084	SCV001756821	pathogenic	not provided	2025-04-23	criteria provided, single submitter	clinical testing	No data available from control populations to assess the frequency of this variant; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 28597072, 31443951, 12754707, 19823873, 16770791, 33050418)
Ambry Genetics	RCV002341259	SCV002619016	likely pathogenic	Cardiovascular phenotype	2020-07-10	criteria provided, single submitter	clinical testing	The c.3432+2036A>G intronic variant results from an A to G substitution 2036 nucleotides after coding exon 25 in the DMD gene. This variant was reported in a Becker muscular dystrophy case with milder phenotype, including elevated serum CK level, proximal muscle weakness, and calf enlargement; RNA studies showed a mix of normal and abnormally spliced transcripts which incorporated an out-of-frame pseudoexon within the intron (Tuffery-Giraud S et al. Hum. Mutat., 2003 Jun;21:608-14). This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create new alternate splice acceptor and donor sites; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
OMIM	RCV000012039	SCV000032273	pathogenic	Becker muscular dystrophy	2003-06-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004537895	SCV004104972	likely pathogenic	DMD-related disorder	2024-01-24	no assertion criteria provided	clinical testing	The DMD c.3432+2036A>G variant is predicted to interfere with splicing. This variant was reported in the hemizygous state in a male patient with subclinical Becker muscular dystrophy (Tuffery-Giraud et al. 2003. PubMed ID: 12754707). mRNA studies in patient's muscle tissue showed that this variant results in the activation of an intronic pseudoexon leading to a frameshift and premature termination codon. Of note, a mixture of normal spliced transcript was also found in the patient's muscle tissues, suggested by the authors explaining a milder phenotype (Tuffery-Giraud et al. 2003. PubMed ID: 12754707). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.