rs62636491
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_001927.4(DES):c.893C>T(p.Ser298Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S298S) has been classified as Likely benign.
Frequency
Consequence
NM_001927.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.893C>T | p.Ser298Leu | missense_variant | 4/9 | ENST00000373960.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.893C>T | p.Ser298Leu | missense_variant | 4/9 | 1 | NM_001927.4 | P1 | |
DES | ENST00000477226.6 | n.367C>T | non_coding_transcript_exon_variant | 3/8 | 4 | ||||
DES | ENST00000492726.1 | n.288C>T | non_coding_transcript_exon_variant | 3/6 | 4 | ||||
DES | ENST00000683013.1 | n.281C>T | non_coding_transcript_exon_variant | 2/7 |
Frequencies
GnomAD3 genomes ? AF: 0.000132 AC: 20AN: 152058Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251194Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135850
GnomAD4 exome AF: 0.000183 AC: 267AN: 1461798Hom.: 0 Cov.: 37 AF XY: 0.000169 AC XY: 123AN XY: 727202
GnomAD4 genome ? AF: 0.000132 AC: 20AN: 152058Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10AN XY: 74272
ClinVar
Submissions by phenotype
not provided Uncertain:4Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 11, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 18, 2020 | - - |
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 11, 2019 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 19, 2022 | - - |
Desmin-related myofibrillar myopathy Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Cardiomyopathy Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jan 03, 2019 | - - |
Dilated cardiomyopathy 1I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Apr 05, 2018 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2021 | 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. - |
Neurogenic scapuloperoneal syndrome, Kaeser type Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at