rs137853030
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001080463.2(DYNC2H1):c.1759C>T(p.Arg587Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,334 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R587H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001080463.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYNC2H1 | NM_001080463.2 | c.1759C>T | p.Arg587Cys | missense_variant | 12/90 | ENST00000650373.2 | |
DYNC2H1 | NM_001377.3 | c.1759C>T | p.Arg587Cys | missense_variant | 12/89 | ENST00000375735.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYNC2H1 | ENST00000650373.2 | c.1759C>T | p.Arg587Cys | missense_variant | 12/90 | NM_001080463.2 | A1 | ||
DYNC2H1 | ENST00000375735.7 | c.1759C>T | p.Arg587Cys | missense_variant | 12/89 | 1 | NM_001377.3 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248368Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134750
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461234Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726880
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74282
ClinVar
Submissions by phenotype
Asphyxiating thoracic dystrophy 3 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 27, 2023 | Variant summary: DYNC2H1 c.1759C>T (p.Arg587Cys) results in a non-conservative amino acid change located in the tail domain (IPR013594) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248368 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1759C>T has been reported in the literature in both compound heterozygous and homozygous individuals affected with Short-rib thoracic dysplasia (e.g., Merrill_2009, Baujat_2013), and the variant was found to segregate with disease in related individuals. These data indicate that the variant is very likely to be associated with disease. At least one publication describes experimental evidence evaluating an impact on protein function, reporting findings consistent with the variant causing a defect in cytoskeletal microtubule architecture (e.g., Merrill_2009). The following publications have been ascertained in the context of this evaluation (PMID: 23339108, 19361615). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 26, 2019 | - - |
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2009 | - - |
Pathogenic, no assertion criteria provided | research | Dan Cohn Lab, University Of California Los Angeles | Jun 01, 2017 | - - |
Jeune thoracic dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 587 of the DYNC2H1 protein (p.Arg587Cys). This variant is present in population databases (rs137853030, gnomAD 0.007%). This missense change has been observed in individuals with short-rib polydactyly syndrome/asphyxiating thoracic dystrophy (PMID: 19361615, 23339108). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6506). 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 DYNC2H1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at