Submissions for variant NM_001927.4(DES):c.725T>A (p.Val242Glu)

dbSNP: rs794728984

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183346	SCV000235779	uncertain significance	not provided	2016-01-19	criteria provided, single submitter	clinical testing	The Val242Glu variant of uncertain significance in the DES gene has not been reported as a pathogenic variantor as a benign variant to our knowledge. Val242Glu results in a non-conservative amino acid substitution of anon-polar Valine with a negatively charged Glutamic acid at a position where only amino acids with similarproperties to Valine are tolerated across species. In silico analysis predicts Val242Glu is probably damaging tothe protein structure/function. Missense variants in nearby residues (Glu245Asp, Glu246Asp) have been reported inHGMD in association with myopathy (Stenson et al., 2014), further supporting the functional importance of thisregion of the protein. Furthermore, the Val242Glu variant was not observed in approximately 6,500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a commonbenign variant in these populations.However, additional evidence is needed to determine whether this variant is pathogenic or benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003765136	SCV004573193	uncertain significance	Desmin-related myofibrillar myopathy	2023-07-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 242 of the DES protein (p.Val242Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32880476). ClinVar contains an entry for this variant (Variation ID: 201701). 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000183346	SCV002033868	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000183346	SCV002035092	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000183346	SCV002037490	uncertain significance	not provided		no assertion criteria provided	clinical testing