ClinVar Miner

Submissions for variant NM_001927.4(DES):c.1258A>C (p.Ile420Leu)

gnomAD frequency: 0.00001  dbSNP: rs1427557970
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001762979 SCV001989025 uncertain significance not provided 2020-01-21 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp RCV002032785 SCV002141429 uncertain significance Desmin-related myofibrillar myopathy 2024-06-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 420 of the DES protein (p.Ile420Leu). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 1303521). 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 not expected to disrupt DES protein function with a negative predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics RCV002503192 SCV002781151 uncertain significance Dilated cardiomyopathy 1I; Desmin-related myofibrillar myopathy; Neurogenic scapuloperoneal syndrome, Kaeser type 2021-07-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV004040073 SCV005018341 uncertain significance Cardiovascular phenotype 2024-03-04 criteria provided, single submitter clinical testing The p.I420L variant (also known as c.1258A>C), located in coding exon 7 of the DES gene, results from an A to C substitution at nucleotide position 1258. The isoleucine at codon 420 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001762979 SCV005875625 uncertain significance not provided 2023-12-18 criteria provided, single submitter clinical testing The DES c.1258A>C; p.Ile420Leu variant (rs1427557970), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 1303521). This variant is found in the general population with an overall allele frequency of 0.0025% (7/282830 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.375). Due to limited information, the clinical significance of this variant is uncertain at this time.

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