Submissions for variant NM_004006.3(DMD):c.10262+1G>A

gnomAD frequency: 0.00069  dbSNP: rs145603325

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723512	SCV000112320	uncertain significance	not provided	2018-01-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000723512	SCV000564939	benign	not provided	2021-05-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30415094, 23871722, 23352160, 26743743, 26990548, 32013268, 30275481)
Invitae	RCV000990563	SCV000625826	benign	Duchenne muscular dystrophy	2024-01-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621654	SCV000737260	likely benign	Cardiovascular phenotype	2019-01-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000778896	SCV000915301	uncertain significance	Dilated cardiomyopathy 3B	2018-11-16	criteria provided, single submitter	clinical testing	The DMD c.10262+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant is reported in one study and found in one deceased individual affected with sudden unexpected death (Schieper et al. 2018). Control data are unavailable for this variant, which is reported at a frequency of 0.001630 in the African population of the Genome Aggregation Database and includes nine hemizygotes in this population and 15 hemizygotes in the Total population. Based on the potential impact of splice donor variants and the limited evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for X-linked dilated cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics	RCV000990563	SCV001141576	likely benign	Duchenne muscular dystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000723512	SCV001143740	benign	not provided	2019-06-27	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000778896	SCV001366470	uncertain significance	Dilated cardiomyopathy 3B	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3. This variant was detected in hemizygous state.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844031	SCV002103725	benign	not specified	2022-02-09	criteria provided, single submitter	clinical testing	Variant summary: DMD c.10262+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 a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00024 in 179061 control chromosomes (including 9 hemizygotes), predominantly at a frequency of 0.0017 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 154-fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (1.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.10262+1G>A has been reported in the literature in male individuals affected with dystrophinopathies, autism spectrum disorder and atrial fibrillation and also, in women with sudden death and peripartum cardiomyopathy (Lim_2013, Kim_2016, Ware_2016, Scheiper_2018, Vad_2020). These reports do not provide unequivocal conclusions about association of the variant with Dystrophinopathies. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.