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.
ClinVar Genomic variation as it relates to human health
NM_001377.3(DYNC2H1):c.1759C>T (p.Arg587Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001377.3(DYNC2H1):c.1759C>T (p.Arg587Cys)
Variation ID: 6506 Accession: VCV000006506.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q22.3 11: 103125197 (GRCh38) [ NCBI UCSC ] 11: 102995926 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 10, 2017 Feb 14, 2024 Nov 28, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001377.3:c.1759C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001368.2:p.Arg587Cys missense NM_001080463.2:c.1759C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001073932.1:p.Arg587Cys missense NC_000011.10:g.103125197C>T NC_000011.9:g.102995926C>T NG_016423.2:g.20767C>T Q8NCM8:p.Arg587Cys - Protein change
- R587C
- Other names
- -
- Canonical SPDI
- NC_000011.10:103125196:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| DYNC2H1 | - | - |
GRCh38 GRCh37 |
3564 | 3597 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 27, 2023 | RCV000006879.19 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 28, 2023 | RCV001851709.11 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Jun 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Asphyxiating thoracic dystrophy 3
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004020773.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
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 … (more)
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. (less)
|
|
|
Likely pathogenic
(Jul 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Asphyxiating thoracic dystrophy 3
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017353.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Jeune thoracic dystrophy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002245353.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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|
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Pathogenic
(Apr 01, 2009)
|
no assertion criteria provided
Method: literature only
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SHORT-RIB THORACIC DYSPLASIA 3 WITH OR WITHOUT POLYDACTYLY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027075.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 13, 2018 |
Comment on evidence:
In 4 affected offspring, born to first-cousin parents (family R01-314), who were clinically diagnosed with short rib-polydactyly syndrome type III (SRTD3; 613091), Merrill et al. … (more)
In 4 affected offspring, born to first-cousin parents (family R01-314), who were clinically diagnosed with short rib-polydactyly syndrome type III (SRTD3; 613091), Merrill et al. (2009) detected homozygosity for a C-to-T transition at nucleotide 1759 in exon 12 of the DYNC2H1 gene, predicted to lead to the amino acid substitution arg587 to cys (R587C). The unaffected parents and sib were heterozygous for the mutation. The authors noted that this family showed phenotypic variability, since the female proband did not have polydactyly, whereas the 3 other sibs exhibited postaxial polydactyly of both hands and feet. (less)
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|
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Asphyxiating thoracic dystrophy 3
Affected status: yes
Allele origin:
inherited
|
University of Washington Center for Mendelian Genomics, University of Washington
Accession: SCV001479736.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
|
|
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Pathogenic
(Jun 01, 2017)
|
no assertion criteria provided
Method: research
|
Asphyxiating thoracic dystrophy 3
Affected status: yes
Allele origin:
paternal,
unknown
|
Dan Cohn Lab, University Of California Los Angeles
Accession: SCV000611927.1
First in ClinVar: Dec 10, 2017 Last updated: Dec 10, 2017 |
Observation 1: Observation 2: |
Comment:
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. | Zhang W | Human mutation | 2018 | PMID: 29068549 |
| Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families. | Baujat G | Journal of medical genetics | 2013 | PMID: 23339108 |
| Ciliary abnormalities due to defects in the retrograde transport protein DYNC2H1 in short-rib polydactyly syndrome. | Merrill AE | American journal of human genetics | 2009 | PMID: 19361615 |
Text-mined citations for rs137853030 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.