Submissions for variant NM_004006.3(DMD):c.9563+1G>A

dbSNP: rs886043989

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726209	SCV000342921	pathogenic	not provided	2016-07-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000274126	SCV000625989	pathogenic	Duchenne muscular dystrophy	2024-09-15	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 65 of the DMD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individuals with DMD-related muscular dystrophy (PMID: 8281150, 20485447, 23536893, 27593222). ClinVar contains an entry for this variant (Variation ID: 288725). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000274126	SCV001141595	pathogenic	Duchenne muscular dystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Suma Genomics	RCV000274126	SCV001837635	pathogenic	Duchenne muscular dystrophy		criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000274126	SCV002769633	pathogenic	Duchenne muscular dystrophy	2022-12-16	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Revvity Omics, Revvity	RCV000726209	SCV003827615	pathogenic	not provided	2023-05-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155153	SCV003844792	pathogenic	Qualitative or quantitative defects of dystrophin	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: DMD c.9563+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: Three predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (example: Lenk_1993). The variant was absent in 183335 control chromosomes (gnomAD). c.9563+1G>A has been reported in the literature in individuals affected with Dystrophinopathies (examples: Lenk_1993, Takeshima_2010, Juan-Mateu_2013, Cho_2017). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics	RCV000726209	SCV004229590	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing	This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. This variant has been identified in multiple unrelated individuals with DMD. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000274126	SCV005086895	pathogenic	Duchenne muscular dystrophy	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Becker muscular dystrophy (MIM#300376), Duchenne muscular dystrophy (MIM#310200) and dilated cardiomyopathy 3B (MIM#302045). (I) 0109 - This gene is associated with X-linked recessive disease. This gene is primarily associated with X-linked recessive disease relating to the muscular dystrophy phenotypes, however it is also associated with X-linked dominant DCM (OMIM, PMID: 26066469). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. PCR studies have shown that this variant causes loss of the canonical donor site and activation of a cryptic donor site which causes the retention of 4 intronic base pairs, resulting in an out of frame protein product (PMID: 10533061). (SP) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0702 - Other splice site variants comparable to the one identified in this case have strong previous evidence for pathogenicity. c.9563+1G>T, c.9563+2T>A and c.9563+5G>C have been classified as pathogenic or likely pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed in several individuals with DMD in the literature (PMIDs: 10533061, 8281150, 23536893). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV000726209	SCV005201810	pathogenic	not provided	2023-11-14	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27350676, 28597072, 25525159, 28152980, 27593222, 10533061, 20485447, 23536893, 28859693, 27363342, 32194622, 34297739, 15351422, 31475473, 8281150)
OMIM	RCV000274126	SCV000032257	pathogenic	Duchenne muscular dystrophy	1993-11-01	no assertion criteria provided	literature only
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	RCV000274126	SCV000882777	pathogenic	Duchenne muscular dystrophy	2019-02-11	no assertion criteria provided	research