rs144908941
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting
The NM_001927.4(DES):c.643G>A(p.Val215Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,082 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).
Frequency
Consequence
NM_001927.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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DES | ENST00000373960.4 | c.643G>A | p.Val215Met | missense_variant | Exon 3 of 9 | 1 | NM_001927.4 | ENSP00000363071.3 | ||
DES | ENST00000477226.6 | n.117G>A | non_coding_transcript_exon_variant | Exon 2 of 8 | 4 | |||||
DES | ENST00000492726.1 | n.38G>A | non_coding_transcript_exon_variant | Exon 2 of 6 | 4 | |||||
DES | ENST00000683013.1 | n.31G>A | non_coding_transcript_exon_variant | Exon 1 of 7 |
Frequencies
GnomAD3 genomes AF: 0.000145 AC: 22AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000596 AC: 15AN: 251468Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135912
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461880Hom.: 0 Cov.: 35 AF XY: 0.0000165 AC XY: 12AN XY: 727238
GnomAD4 genome AF: 0.000145 AC: 22AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:4
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Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 222542) -
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Desmin-related myofibrillar myopathy Uncertain:1
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 215 of the DES protein (p.Val215Met). This variant is present in population databases (rs144908941, gnomAD 0.04%). 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: 222542). Invitae Evidence 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 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. -
Dilated cardiomyopathy 1I Uncertain:1
The c.643G>A (p.Val215Met) variant identified in the DES gene substitutes a well conserved Valine for Methionine at amino acid 215/471 (exon 3/9).This variant is found with low frequency in gnomAD(v3.1.2)(22 heterozygotes, 0 homozygotes; allele frequency:1.45e-4) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.028) and Pathogenic (REVEL; score:0.782) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:222542), and to our current knowledge has not been reported in affected individuals in the literature. The p.Val215 residue is within Coil 1B domain of DES (UniProtKB:P17661). Given the lack of compelling evidence for its pathogenicity, the c.643G>A (p.Val215Met) variant identified in the DES gene is reported as a Variant of Uncertain Significance. -
Desmin-related myofibrillar myopathy;C1858154:Dilated cardiomyopathy 1I;C1867005:Neurogenic scapuloperoneal syndrome, Kaeser type Uncertain:1
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Primary familial hypertrophic cardiomyopathy Uncertain:1
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DES-related disorder Uncertain:1
The DES c.643G>A variant is predicted to result in the amino acid substitution p.Val215Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.044% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-220284976-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Cardiovascular phenotype Uncertain:1
The p.V215M variant (also known as c.643G>A), located in coding exon 3 of the DES gene, results from a G to A substitution at nucleotide position 643. The valine at codon 215 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not specified Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at