rs57965306
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3
The NM_001927.4(DES):c.1049G>A(p.Arg350Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,984 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R350W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001927.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.1049G>A | p.Arg350Gln | missense_variant | 6/9 | ENST00000373960.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.1049G>A | p.Arg350Gln | missense_variant | 6/9 | 1 | NM_001927.4 | P1 | |
DES | ENST00000477226.6 | n.523G>A | non_coding_transcript_exon_variant | 5/8 | 4 | ||||
DES | ENST00000492726.1 | n.444G>A | non_coding_transcript_exon_variant | 5/6 | 4 | ||||
DES | ENST00000683013.1 | n.437G>A | non_coding_transcript_exon_variant | 4/7 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251410Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135888
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461862Hom.: 0 Cov.: 31 AF XY: 0.0000481 AC XY: 35AN XY: 727230
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 16, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 08, 2019 | - - |
Desmin-related myofibrillar myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 350 of the DES protein (p.Arg350Gln). This variant is present in population databases (rs57965306, gnomAD 0.005%). This missense change has been observed in individual(s) with centronuclear myopathy and/or suffered a sudden unexplained death (PMID: 29382405, 29915097). ClinVar contains an entry for this variant (Variation ID: 596421). 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. This variant disrupts the p.Arg350 amino acid residue in DES. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15800015, 17439987, 20448486, 25394388, 27393313). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Desmin-related myofibrillar myopathy;C1858154:Dilated cardiomyopathy 1I;C1867005:Neurogenic scapuloperoneal syndrome, Kaeser type Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 19, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2021 | The p.R350Q variant (also known as c.1049G>A), located in coding exon 6 of the DES gene, results from a G to A substitution at nucleotide position 1049. The arginine at codon 350 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a sudden unexplained death cohort in an individual with an additional alteration in a different cardiac-related gene (Shanks GW et al. Circulation, 2018 06;137:2705-2715). Additionally, this alteration has been reported in an individual with proximal muscle weakness and centronuclear myopathy identified on biopsy (Wu L et al. Can J Neurol Sci, 2018 05;45:262-268). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at