chr2-219420906-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_001927.4(DES):c.976C>T(p.His326Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,708 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H326R) has been classified as Uncertain significance.
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.976C>T | p.His326Tyr | missense_variant | 5/9 | ENST00000373960.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.976C>T | p.His326Tyr | missense_variant | 5/9 | 1 | NM_001927.4 | P1 | |
DES | ENST00000477226.6 | n.450C>T | non_coding_transcript_exon_variant | 4/8 | 4 | ||||
DES | ENST00000492726.1 | n.371C>T | non_coding_transcript_exon_variant | 4/6 | 4 | ||||
DES | ENST00000683013.1 | n.364C>T | non_coding_transcript_exon_variant | 3/7 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461708Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1AN XY: 727146
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Desmin-related myofibrillar myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 326 of the DES protein (p.His326Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of arrhythmogenic cardiomyopathy (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 201705). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 18, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 03, 2018 | The H326Y has not been published as a pathogenic variant or as a benign variant to our knowledge. The H326Y variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H326Y variant is a non-conservative amino acid substitution, which is more likely to impact secondary protein structure as these residues differ in charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense variant in a nearby residue (D336Y) has been reported in the Human Gene Mutation Database in association with desmin related myopathy (Stenson et al., 2014).Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign . - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at