Submissions for variant NM_001927.4(DES):c.1A>G (p.Met1Val)

dbSNP: rs1057523274

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000417495	SCV000531325	likely pathogenic	not provided	2024-10-30	criteria provided, single submitter	clinical testing	Identified heterozygous in patients with ARVC and DCM in published literature (PMID: 36264615); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36264615)
Genetic Services Laboratory, University of Chicago	RCV001217218	SCV000594355	likely pathogenic	Desmin-related myofibrillar myopathy	2016-12-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001217218	SCV001389052	likely pathogenic	Desmin-related myofibrillar myopathy	2024-08-31	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the DES mRNA. The next in-frame methionine is located at codon 263. This variant is not present in population databases (gnomAD no frequency). 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: 388926). This variant disrupts head, Coil 1A, and Coil 1B domains of the DES protein, which are important for desmin-mitochondrial interaction (PMID: 33825342, 15477095) . While functional studies have not been performed to directly test the effect of this variant on DES protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV004609380	SCV005107277	uncertain significance	Cardiovascular phenotype	2024-05-17	criteria provided, single submitter	clinical testing	The p.M1? variant (also known as c.1A>G) is located in coding exon 1 of the DES gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Although biallelic loss of function of DES has been associated with autosomal recessive DES-related myofibrillar myopathy, haploinsufficiency of DES has not been established as a mechanism of disease for autosomal dominant DES-related myopathy. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive DES-related myofibrillar myopathy when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant DES-related myopathy is unclear.