Submissions for variant NM_004006.3(DMD):c.4233+2C>T

gnomAD frequency: 0.00066  dbSNP: rs147474070

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000080605	SCV000112507	likely benign	not specified	2015-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000710122	SCV000235870	benign	not provided	2020-03-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17259292, 23871722, 26185613, 25163546, 28701297, 31216405)
Ambry Genetics	RCV000243182	SCV000319745	benign	Cardiovascular phenotype	2018-09-20	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Invitae	RCV000467777	SCV000560844	benign	Duchenne muscular dystrophy	2024-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710122	SCV000613122	benign	not provided	2016-12-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000467777	SCV000992859	likely benign	Duchenne muscular dystrophy	2017-12-31	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000853040	SCV000995797	benign	Cardiomyopathy	2018-11-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000467777	SCV001141691	likely benign	Duchenne muscular dystrophy	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710122	SCV001155964	likely benign	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001167970	SCV001330523	uncertain significance	Dilated cardiomyopathy 3B	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000710122	SCV001473202	likely benign	not provided	2019-12-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000080605	SCV002556246	benign	not specified	2022-06-29	criteria provided, single submitter	clinical testing	Variant summary: DMD c.4233+2C>T is located in a canonical splice-site and is predicted by several computational tools to strengthen a canonical 5 donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00065 in 182827 control chromosomes in the gnomAD database, including 1 homozygote and 43 hemizygotes. The observed variant frequency is approximately 59-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 benign. c.4233+2C>T has been reported in the literature in individuals affected with dilated cardiomyopathy and vacuolar myopathy, without strong evidence for causality (e.g. Haas_2015, Bodian_2017, Mair_2020). In at least one of these reports the variant was also detected in an unaffected parent of the proband. 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. Eleven ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004537359	SCV004755405	likely benign	DMD-related disorder	2019-06-24	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000710122	SCV001962754	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000710122	SCV001963721	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831849	SCV002085347	likely benign	Becker muscular dystrophy; Duchenne muscular dystrophy; Cardiomyopathy; Dystrophin deficiency	2017-10-18	no assertion criteria provided	clinical testing