Submissions for variant NM_001927.4(DES):c.893C>T (p.Ser298Leu)

gnomAD frequency: 0.00014  dbSNP: rs62636491

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171830	SCV000055125	uncertain significance	Primary dilated cardiomyopathy	2018-04-05	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000056814	SCV000335234	uncertain significance	not provided	2015-09-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000056814	SCV000491114	uncertain significance	not provided	2019-04-11	criteria provided, single submitter	clinical testing	Reported previously in a patient with DCM but no reported myopathy; however segregation data were not provided (Taylor et al., 2007); Functional studies show disruption of desmin filament assembly in the presence of the S298L variant (Taylor et al., 2007); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30564623, 23299917, 23861362, 17325244, 23143191, 22337857, 20474083, 27896284, 29926427)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466593	SCV000552184	uncertain significance	Desmin-related myofibrillar myopathy	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 298 of the DES protein (p.Ser298Leu). This variant is present in population databases (rs62636491, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 17325244, 23861362). ClinVar contains an entry for this variant (Variation ID: 66423). 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) has been performed at Invitae 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. 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.
Illumina Laboratory Services, Illumina	RCV001142372	SCV001302806	uncertain significance	Dilated cardiomyopathy 1I	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000466593	SCV001302807	benign	Desmin-related myofibrillar myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001143228	SCV001303735	benign	Neurogenic scapuloperoneal syndrome, Kaeser type	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Athena Diagnostics	RCV000056814	SCV001475073	uncertain significance	not provided	2020-03-18	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000056814	SCV003829066	uncertain significance	not provided	2022-08-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003352761	SCV004056210	uncertain significance	Cardiovascular phenotype	2021-06-16	criteria provided, single submitter	clinical testing	The c.893C>T (p.S298L) alteration is located in exon 4 (coding exon 4) of the DES gene. This alteration results from a C to T substitution at nucleotide position 893, causing the serine (S) at amino acid position 298 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000056814	SCV000087927	not provided	not provided		no assertion provided	not provided
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000735983	SCV000864165	likely pathogenic	Cardiomyopathy	2019-01-03	no assertion criteria provided	clinical testing