rs766035912
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_001927.4(DES):c.974G>A(p.Arg325Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,658 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R325R) 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 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.974G>A | p.Arg325Gln | missense_variant | 5/9 | ENST00000373960.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.974G>A | p.Arg325Gln | missense_variant | 5/9 | 1 | NM_001927.4 | P1 | |
DES | ENST00000477226.6 | n.448G>A | non_coding_transcript_exon_variant | 4/8 | 4 | ||||
DES | ENST00000492726.1 | n.369G>A | non_coding_transcript_exon_variant | 4/6 | 4 | ||||
DES | ENST00000683013.1 | n.362G>A | non_coding_transcript_exon_variant | 3/7 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251108Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135758
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461658Hom.: 0 Cov.: 38 AF XY: 0.00000688 AC XY: 5AN XY: 727128
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 19, 2014 | The p.Arg325Gln variant in DES has not been previously reported in individuals w ith cardiomyopathy. It has been detected in 1/16,482 South Asian chromosomes sc reened by the Broad Institute (http://exac.broadinstitute.org/). The affected am ino acid is conserved in evolution, suggesting that a change may not be tolerate d. However, this is not predictive enough to imply pathogenicity. In summary, t he clinical significance of the p.Arg325Gln variant is uncertain. - |
Desmin-related myofibrillar myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 29, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 325 of the DES protein (p.Arg325Gln). This variant is present in population databases (rs766035912, gnomAD 0.006%). 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: 228554). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 15, 2023 | The p.R325Q variant (also known as c.974G>A), located in coding exon 5 of the DES gene, results from a G to A substitution at nucleotide position 974. The arginine at codon 325 is replaced by glutamine, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at