ClinVar Miner

Submissions for variant NM_004006.3(DMD):c.1812+1G>A

gnomAD frequency: 0.00003  dbSNP: rs373286166
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000521440 SCV000255707 pathogenic not provided 2014-08-04 criteria provided, single submitter clinical testing
GeneDx RCV000521440 SCV000616994 pathogenic not provided 2022-01-25 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); Destroys the canonical splice donor site in intron 15, and cDNA analysis confirms that c.1812+1 G>A results in the in-frame skipping of exon 15 (Lerario et al., 2016); This variant is associated with the following publications: (PMID: 23871722, 25637381, 25525159, 27930565, 17259292, 32194622, 33726816, 33101180)
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000201160 SCV000692204 pathogenic Duchenne muscular dystrophy 2017-02-07 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital RCV000149882 SCV000692205 pathogenic Becker muscular dystrophy 2017-02-07 criteria provided, single submitter clinical testing
Invitae RCV000201160 SCV001205869 pathogenic Duchenne muscular dystrophy 2023-12-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 15 of the DMD gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs373286166, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with Becker or Duchenne muscular dystrophy (PMID: 17259292, 19937601, 27930565, 32194622). ClinVar contains an entry for this variant (Variation ID: 162497). Studies have shown that disruption of this splice site results in skipping of exon 15, but is expected to preserve the integrity of the reading-frame (PMID: 27930565). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000521440 SCV001962614 pathogenic not provided 2022-11-01 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000149882 SCV002579670 likely pathogenic Becker muscular dystrophy 2022-04-22 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV000201160 SCV002761495 pathogenic Duchenne muscular dystrophy 2021-01-14 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002483296 SCV002777815 pathogenic Becker muscular dystrophy; Duchenne muscular dystrophy; Dilated cardiomyopathy 3B 2022-03-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155089 SCV003844269 pathogenic Qualitative or quantitative defects of dystrophin 2023-02-27 criteria provided, single submitter clinical testing Variant summary: DMD c.1812+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 182866 control chromosomes (gnomAD). c.1812+1G>A has been reported in the literature in individuals affected with Dystrophinopathies (example: Taylor_2007, Neri_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. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000149882 SCV004194010 pathogenic Becker muscular dystrophy 2022-02-01 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000149882 SCV000190163 likely pathogenic Becker muscular dystrophy 2014-06-01 no assertion criteria provided research
Counsyl RCV000149882 SCV001132169 likely pathogenic Becker muscular dystrophy 2018-12-07 no assertion criteria provided clinical testing
Counsyl RCV000984163 SCV001132170 likely pathogenic Dilated cardiomyopathy 3B 2018-12-07 no assertion criteria provided clinical testing
Counsyl RCV000201160 SCV001132171 likely pathogenic Duchenne muscular dystrophy 2018-12-07 no assertion criteria provided clinical testing
Natera, Inc. RCV001826801 SCV002092233 pathogenic Becker muscular dystrophy; Duchenne muscular dystrophy; Cardiomyopathy; Dystrophin deficiency 2020-10-22 no assertion criteria provided clinical testing

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