ClinVar Miner

Submissions for variant NM_001927.4(DES):c.1063C>T (p.Arg355Ter)

gnomAD frequency: 0.00001  dbSNP: rs762808690
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000755704 SCV000883140 uncertain significance Dilated cardiomyopathy 1I 2018-11-21 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001784366 SCV002024044 likely pathogenic not provided 2022-12-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV002406675 SCV002714681 uncertain significance Cardiovascular phenotype 2022-02-03 criteria provided, single submitter clinical testing The p.R355* variant (also known as c.1063C>T), located in coding exon 6 of the DES gene, results from a C to T substitution at nucleotide position 1063. This changes the amino acid from an arginine to a stop codon within coding exon 6. This variant has been reported as a secondary finding in a whole exome sequencing cohort; however, clinical details were limited (Thauvin-Robinet C et al. Eur J Hum Genet, 2019 08;27:1197-1214). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Although biallelic loss of function alterations in DES have been associated with autosomal recessive DES-related myopathy, haploinsufficiency for DES has not been clearly established as a mechanism of disease for autosomal dominant DES-related myopathy. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017725 SCV004847600 likely pathogenic Desmin-related myofibrillar myopathy 2019-02-08 criteria provided, single submitter clinical testing The p.Arg355X variant in DES has not been previously reported in individuals with desmin-related myopathy but has been identified in 1/113718 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 355, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the DES gene is an established disease mechanism in desmin-related myopathy. In summary, although additional studies are required to fully establish its clinical significance, the p.Gln355X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.

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