Submissions for variant NM_001927.4(DES):c.638C>T (p.Ala213Val)

gnomAD frequency: 0.01015  dbSNP: rs41272699

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000037245	SCV000051520	benign	not specified	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037245	SCV000060902	benign	not specified	2012-01-10	criteria provided, single submitter	clinical testing	Ala213Val in exon 2 of DES: This variant has been reported by several studies an d was initially thought to be disease causing (Goldfarb 2004, Bar 2004, Kostarev a 2006). However, it has been identified in 0.4% (8/2000) of chromosomes from a broad, though clinically and racially unspecified population (dbSNP rs41272699) and in 1.5% (102/7020) of European American chromosomes and 0.4% (14/3738) of Af rican American chromosomes by the NHBLI Exome sequencing project in a clinical c ohort that included individuals with heart disease (http://evs.gs.washington.edu /EVS). With a frequency this high the variant is considered to be benign.
Eurofins Ntd Llc (ga)	RCV000037245	SCV000111847	benign	not specified	2013-06-04	criteria provided, single submitter	clinical testing
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000203295	SCV000258325	uncertain significance	Congenital diaphragmatic hernia	2015-03-03	criteria provided, single submitter	research	It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family.
Invitae	RCV001083932	SCV000287227	benign	Desmin-related myofibrillar myopathy	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000037245	SCV000308542	benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000250294	SCV000318135	benign	Cardiovascular phenotype	2015-09-15	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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	RCV000313133	SCV000427698	likely benign	Dilated cardiomyopathy 1I	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000367823	SCV000427699	likely benign	Neurogenic scapuloperoneal syndrome, Kaeser type	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000263666	SCV000427700	likely benign	Myofibrillar Myopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001083932	SCV000427701	likely benign	Desmin-related myofibrillar myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Athena Diagnostics Inc	RCV000037245	SCV000613090	likely benign	not specified	2017-08-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000056805	SCV000885275	benign	not provided	2023-10-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037245	SCV000919258	benign	not specified	2018-09-03	criteria provided, single submitter	clinical testing	Variant summary: DES c.638C>T (p.Ala213Val) results in a non-conservative amino acid change located in the Intermediate filament, rod domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0094 in 278984 control chromosomes in the gnomAD database, including 28 homozygotes. The observed variant frequency is approximately 375 fold of the estimated maximal expected allele frequency for a pathogenic variant in DES causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.638C>T has been reported in the literature in individuals affected with Cardiomyopathy as well as in controls. In one study, the variant failed to segregate with disease in a family, being found in 4 healthy individuals and was absent in 1 affected individual (Taylor_2007). In functional studies, cells expressing the variant showed normal complete filamentous network (Bar_2005, Goudeau_2006). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001171067	SCV001333737	likely benign	Cardiomyopathy	2023-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000056805	SCV001844700	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 33232181, 32105824, 22215463, 25736269, 17325244, 23861362, 20474083, 27618136, 22260945, 16865695, 21842594, 25617006, 23168288)
Molecular Genetics, Royal Melbourne Hospital	RCV001083932	SCV002503635	benign	Desmin-related myofibrillar myopathy	2020-11-20	criteria provided, single submitter	clinical testing	European (non-Finnish) population allele frequency is 1.5% (rs41272699, 1,953/129,178 alleles, 20 homozygotes in gnomAD v2.1). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056805	SCV000087918	not provided	not provided		no assertion provided	not provided
Wellcome Centre for Mitochondrial Research, Newcastle University	RCV000239721	SCV000298017	pathogenic	Myofibrillar myopathy	2016-08-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000056805	SCV001740997	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000037245	SCV001922672	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000056805	SCV001932939	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000037245	SCV001955208	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000037245	SCV001975788	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000056805	SCV002036158	likely benign	not provided		no assertion criteria provided	clinical testing