Submissions for variant NM_001927.4(DES):c.1217G>A (p.Arg406Gln)

gnomAD frequency: 0.00001  dbSNP: rs1057520275

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000437250	SCV000512796	uncertain significance	not provided	2023-09-27	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001313201	SCV001503685	uncertain significance	Desmin-related myofibrillar myopathy	2024-08-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 406 of the DES protein (p.Arg406Gln). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 377769). Invitae Evidence 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 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. This variant disrupts the p.Arg406 amino acid residue in DES. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10717012, 10905661, 14991347). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Ambry Genetics	RCV002356524	SCV002655805	uncertain significance	Cardiovascular phenotype	2021-10-04	criteria provided, single submitter	clinical testing	The p.R406Q variant (also known as c.1217G>A), located in coding exon 6 of the DES gene, results from a G to A substitution at nucleotide position 1217. This variant was detected in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC); however, this individual was also reported to have a PKP2 frameshift variant (Orgeron GM et al. J Am Heart Assoc, 2017 Jun;6:[Epub ahead of print]; Assis FR et al. Heart Rhythm, 2019 07;16:1003-1010). The arginine at codon 406 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002488876	SCV002783848	uncertain significance	Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type	2022-03-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409586	SCV004116382	uncertain significance	DES-related disorder	2022-09-17	criteria provided, single submitter	clinical testing	The DES c.1217G>A variant is predicted to result in the amino acid substitution p.Arg406Gln. To our knowledge, this variant has not been reported in the literature. However, a different substitution at the same codon c.1216C>T (p.Arg406Trp) has been reported to be pathogenic for desmin related myopathy (Dalakas et al. 2000. PubMed ID: 10717012; Punetha et al. 2016. PubMed ID: 27854218, https://www.ncbi.nlm.nih.gov/clinvar/variation/16826/). Another different substitution at the same codon c.1217G>T (p.Arg406Leu) was reported as likely pathogenic in 2015 (https://www.ncbi.nlm.nih.gov/clinvar/variation/972950/). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-220286255-G-A) and interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/377769/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.