Submissions for variant NM_001927.4(DES):c.985C>T (p.Gln329Ter)

dbSNP: rs759320891

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000622709	SCV000740501	likely pathogenic	Arrhythmogenic right ventricular cardiomyopathy	2016-09-29	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV002223889	SCV002502859	likely pathogenic	not provided	2022-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265821	SCV002548222	likely pathogenic	Cardiomyopathy	2022-05-06	criteria provided, single submitter	clinical testing	Variant summary: DES c.985C>T (p.Gln329X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 4e-06 in 251050 control chromosomes (gnomAD). To our knowledge, no occurrence of c.985C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002385957	SCV002691217	uncertain significance	Cardiovascular phenotype	2024-08-14	criteria provided, single submitter	clinical testing	The p.Q329* variant (also known as c.985C>T), located in coding exon 5 of the DES gene, results from a C to T substitution at nucleotide position 985. This changes the amino acid from a glutamine to a stop codon within coding exon 5. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531873	SCV003461764	pathogenic	Desmin-related myofibrillar myopathy	2024-10-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln329*) in the DES gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DES are known to be pathogenic (PMID: 23575897). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 520492). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV002531873	SCV004847599	likely pathogenic	Desmin-related myofibrillar myopathy	2019-02-08	criteria provided, single submitter	clinical testing	The p.Gln329X variant in DES has not been previously reported in individuals with desmin-related myopathy but has been reported in ClinVar (Variation ID: 520492). This variant has been identified in 1/113572 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 329, 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.Gln329X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2.