Submissions for variant NM_001927.4(DES):c.170C>T (p.Ser57Leu)

gnomAD frequency: 0.00077  dbSNP: rs372825868

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037234	SCV000060891	uncertain significance	not specified	2014-09-30	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Ser57Leu varian t in DES has been previously identified by our laboratory in 1 toddler with LVNC and 1 teenager with reduced LV function. This variant has also been identified in 0.1% (4/4142) of African American chromosomes by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS/; dbSNP rs372825868). Computational pre diction tools and conservation analysis suggest this variant may impact the prot ein, though this information is not predictive enough to determine pathogenicity . In summary, while the clinical significance of the Ser57Leu variant is uncerta in, its frequency suggests that it is more likely to be benign.
GeneDx	RCV000586931	SCV000235798	uncertain significance	not provided	2022-10-06	criteria provided, single submitter	clinical testing	Functional studies showed p.(S57L) results in similar desmin aggregates but different location of the protein compared to wild type (Kubanek et al. 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30564623, 20718792, 26272908, 32235386)
Eurofins Ntd Llc (ga)	RCV000586931	SCV000333306	uncertain significance	not provided	2018-05-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000037234	SCV000603295	uncertain significance	not specified	2017-02-16	criteria provided, single submitter	clinical testing
Invitae	RCV000547047	SCV000654170	uncertain significance	Desmin-related myofibrillar myopathy	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 57 of the DES protein (p.Ser57Leu). This variant is present in population databases (rs372825868, gnomAD 0.1%). This missense change has been observed in individual(s) with sudden unexpected death and dilated cardiomyopathy (PMID: 26272908, 32235386). ClinVar contains an entry for this variant (Variation ID: 44254). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DES protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037234	SCV000697879	likely benign	not specified	2023-03-01	criteria provided, single submitter	clinical testing	Variant summary: DES c.170C>T (p.Ser57Leu) results in a non-conservative amino acid change located in the Intermediate filament head, DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 218216 control chromosomes. The observed variant frequency is approximately 12 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.170C>T has been reported in the literature in individuals affected with Cardiomyopathy. These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign n=1, VUS n=6). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000621896	SCV000736902	likely benign	Cardiovascular phenotype	2022-12-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000547047	SCV001297354	uncertain significance	Desmin-related myofibrillar myopathy	2018-01-12	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.
Illumina Laboratory Services, Illumina	RCV001142158	SCV001302568	benign	Neurogenic scapuloperoneal syndrome, Kaeser type	2018-01-12	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	RCV001142159	SCV001302569	uncertain significance	Dilated cardiomyopathy 1I	2018-01-12	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.
Revvity Omics, Revvity	RCV000586931	SCV003829016	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000586931	SCV001742149	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000586931	SCV001924141	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586931	SCV001966396	uncertain significance	not provided		no assertion criteria provided	clinical testing