Submissions for variant NM_001927.4(DES):c.578+11G>A

gnomAD frequency: 0.06130  dbSNP: rs111548596

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037243	SCV000060900	benign	not specified	2011-09-28	criteria provided, single submitter	clinical testing	This variant is classified as benign because it is located in the intron outside the splice consensus and occurs in the general population at a frequency of >1% (rs111548596).
Eurofins Ntd Llc (ga)	RCV000037243	SCV000202613	benign	not specified	2013-12-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000037243	SCV000308540	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000336446	SCV000427690	benign	Myofibrillar Myopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV002054650	SCV000427691	benign	Desmin-related myofibrillar myopathy	2018-01-13	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000282624	SCV000427692	benign	Dilated cardiomyopathy 1I	2018-01-13	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000349318	SCV000427693	benign	Neurogenic scapuloperoneal syndrome, Kaeser type	2018-01-13	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037243	SCV001361553	benign	not specified	2019-09-16	criteria provided, single submitter	clinical testing	Variant summary: DES c.578+11G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.012 in 132482 control chromosomes, predominantly at a frequency of 0.2 within the African or African-American subpopulation in the gnomAD database, including 130 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is well above the estimated maximal expected allele frequency for a pathogenic variant in DES causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Co-occurrences with other pathogenic variant(s) have been reported (TTR c.424G>A), providing supporting evidence for a benign role. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001675591	SCV001892567	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Invitae	RCV002054650	SCV002373388	benign	Desmin-related myofibrillar myopathy	2024-02-01	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000037243	SCV001923380	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000037243	SCV001956998	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000037243	SCV001974026	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001675591	SCV002035427	likely benign	not provided		no assertion criteria provided	clinical testing