Submissions for variant NM_001927.4(DES):c.216C>A (p.Ser72Arg)

gnomAD frequency: 0.00008  dbSNP: rs375719734

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000710118	SCV000224366	uncertain significance	not provided	2015-04-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463940	SCV000552169	uncertain significance	Desmin-related myofibrillar myopathy	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 72 of the DES protein (p.Ser72Arg). This variant is present in population databases (rs375719734, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DES-related conditions. ClinVar contains an entry for this variant (Variation ID: 193219). 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.
Athena Diagnostics	RCV000710118	SCV000613087	uncertain significance	not provided	2018-02-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002265658	SCV000896934	uncertain significance	Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001330866	SCV001522700	uncertain significance	Neurogenic scapuloperoneal syndrome, Kaeser type	2019-11-04	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000710118	SCV001713262	uncertain significance	not provided	2019-04-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000710118	SCV001767778	uncertain significance	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Reported in a stillborn delivered at 41 weeks gestational age who underwent exome analysis (Sahlin et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26807690, 30764827, 30564623, 30615648, 31953240)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001706118	SCV001821356	likely benign	not specified	2022-09-26	criteria provided, single submitter	clinical testing	Variant summary: DES c.216C>A (p.Ser72Arg) results in a non-conservative amino acid change located in the Intermediate filament head, DNA-binding domain (IPR006821) 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 0.00012 in 183438 control chromosomes. The observed variant frequency is approximately 3.84 fold of the estimated maximal expected allele frequency for a pathogenic variant in DES causing Dilated Cardiomyopathy phenotype (3.1e-05), strongly suggesting that the variant is benign. c.216C>A has been reported in the literature in a stillbirth case (Sahlin_2019) and in a family affected with muscular dystrophy, following whole exome sequencing (Dardas_2020). The variant was also detected in only one of two brothers affected with hypertrophic cardiomyopathy and therefore, did not appear to segregate with disease (Refaat_2019). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.1504C>T, p.Arg502Trp; Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798625	SCV002043132	uncertain significance	Cardiomyopathy	2019-10-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426827	SCV002729227	uncertain significance	Cardiovascular phenotype	2023-11-29	criteria provided, single submitter	clinical testing	The p.S72R variant (also known as c.216C>A), located in coding exon 1 of the DES gene, results from a C to A substitution at nucleotide position 216. The serine at codon 72 is replaced by arginine, an amino acid with dissimilar properties. This variant was detected in an individual with hypertrophic cardiomyopathy (HCM), who had additional cardiac variants detected; his similarly affected brother with HCM did not carry this DES variant (Refaat MM et al. BMC Med Genomics, 2019 02;12:33). This variant was also detected in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC) from a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant has also been detected in a consanguineous family with muscular dystrophy phenotype in whom additional variants were also detected (Dardas Z et al. Eur J Med Genet. 2020 Apr;63(4):103845). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000710118	SCV003829046	uncertain significance	not provided	2022-02-14	criteria provided, single submitter	clinical testing