rs1057518083
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001376.5(DYNC1H1):c.2327C>T(p.Pro776Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P776RV) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001376.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYNC1H1 | NM_001376.5 | c.2327C>T | p.Pro776Leu | missense_variant | 8/78 | ENST00000360184.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYNC1H1 | ENST00000360184.10 | c.2327C>T | p.Pro776Leu | missense_variant | 8/78 | 1 | NM_001376.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures Pathogenic:4
Likely pathogenic, no assertion criteria provided | clinical testing | Département de Neurologie, Hospices Civils de Lyon | Feb 24, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372934). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26846447). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Mar 16, 2018 | The c.2327C>T variant in the DYNC1H1 gene has been reported previously (PMCID:4742772). The patient and his 2 similarly affected identical twin brothers were found to carry the variant. The father was mosaic for this variant with mild symptoms. - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jun 24, 2021 | PS2, PP2, PP3, PM1, PM2, PS4_Moderate - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 28, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 28, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31607746, 26846447, 28554554, 32703465, 26100331, 25609763, 25512093, 35899263, 33060286) - |
Charcot-Marie-Tooth disease axonal type 2O Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 28, 2023 | For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt DYNC1H1 protein function. ClinVar contains an entry for this variant (Variation ID: 372934). This missense change has been observed in individual(s) with lower extremity predominant spinal muscular atrophy (PMID: 26846447, 28554554). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 776 of the DYNC1H1 protein (p.Pro776Leu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at