Submissions for variant NM_001927.4(DES):c.380G>C (p.Arg127Pro)

dbSNP: rs397516694

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037239	SCV000060896	uncertain significance	not specified	2012-08-27	criteria provided, single submitter	clinical testing	The Arg127Pro variant in DES has not been reported in the literature nor previou sly identified by our laboratory. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the c linical significance of this variant.
GeneDx	RCV000183371	SCV000235811	likely pathogenic	not provided	2014-03-13	criteria provided, single submitter	clinical testing	p.Arg127Pro (CGC>CCC): c.380 G>C in exon 1 of the DES gene (NM_001927.3) The R127P variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R127P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R127P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense mutations in nearby residues (N116S, A120D) have been reported in a gene specific database in association with arrhythmogenic right ventricular cardiomyopathy (Van der Zwaag P et al., 2009), supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in CARDIOMYOPATHY panel(s).
Invitae	RCV000547988	SCV000654173	uncertain significance	Desmin-related myofibrillar myopathy	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 127 of the DES protein (p.Arg127Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 25179549). ClinVar contains an entry for this variant (Variation ID: 44259). 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) performed at Invitae indicates that this missense variant is expected to disrupt DES protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects DES function (PMID: 25179549). 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852536	SCV000995234	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2019-03-18	criteria provided, single submitter	clinical testing