VCV000446536.15 - ClinVar

NM_001377.3(DYNC2H1):c.10042+2T>G

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

3 out of 8 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001377.3(DYNC2H1):c.10042+2T>G

Variation ID: 446536 Accession: VCV000446536.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 103245376 (GRCh38) [ NCBI UCSC ] 11: 103116105 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 15, 2026	Dec 1, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001377.3:c.10042+2T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001080463.2:c.10063+2T>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NC_000011.10:g.103245376T>G
NC_000011.9:g.103116105T>G
NG_016423.2:g.140946T>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000011.10:103245375:T:G

Global minor allele frequency (GMAF) Help The 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 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00004

Links

ClinGen: CA382246199 dbSNP: rs1261505725 VarSome

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
Gene	OMIM	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		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	4240	4274

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.
Short-rib thoracic dysplasia 6 with or without polydactyly	Pathogenic/Likely pathogenic (2)	no assertion criteria provided	Jun 1, 2017	RCV000516017.9
Asphyxiating thoracic dystrophy 3	Likely pathogenic (3)	criteria provided, single submitter	Feb 27, 2024	RCV001291173.10
Autosomal recessive polycystic kidney disease	Pathogenic (1)	no assertion criteria provided	Jul 6, 2018	RCV001328199.8
Jeune thoracic dystrophy	Pathogenic (1)	criteria provided, single submitter	Dec 1, 2025	RCV001857881.15
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 22, 2022	RCV003159657.8

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.	Expand all rows Collapse all rows 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.
Pathogenic (Sep 22, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV003915213.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Comment: show Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29068549, 30773290) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Feb 27, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Asphyxiating thoracic dystrophy 3	Fulgent Genetics, Fulgent Genetics Accession: SCV005678359.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Dec 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Jeune thoracic dystrophy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002140717.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Publications: PubMed (5) PubMed: 16199547‚ 23339108‚ 29068549‚ 32753734‚ 33755199 Comment: show This sequence change affects a donor splice site in intron 66 of the DYNC2H1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DYNC2H1 are known to be pathogenic (PMID: 23339108, 32753734, 33755199). This variant is present in population databases (no rsID available, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with short-rib polydactyly syndrome (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446536). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jun 01, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Short-rib thoracic dysplasia 6 with or without polydactyly	Dan Cohn Lab, University Of California Los Angeles Accession: SCV000611909.1 First in ClinVar: Dec 10, 2017 Last updated: Dec 10, 2017	Publications: PubMed (1) PubMed: 29068549 Observation: 1 Collection method: research Allele origin: maternal Affected status: yes Observation 1 Collection method: research Allele origin: maternal Affected status: yes

Pathogenic (Jun 01, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Asphyxiating thoracic dystrophy 3	Dan Cohn Lab, University Of California Los Angeles Accession: SCV000611982.1 First in ClinVar: Dec 10, 2017 Last updated: Dec 10, 2017	Publications: PubMed (1) PubMed: 29068549 Observation: 1 Collection method: research Allele origin: maternal Affected status: yes Observation 1 Collection method: research Allele origin: maternal Affected status: yes

Pathogenic (Jul 06, 2018) N Not contributing to aggregate classification	no assertion criteria provided	Autosomal recessive polycystic kidney disease	Sydney Genome Diagnostics, Children's Hospital Westmead Accession: SCV001449317.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: show This individual is heterozygous for the c.10063+2T>G variant in the DYNC2H1 gene. To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. However, this variant has been submitted as pathogenic on ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/446536/). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.0013% (3 out of 227,450 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) predicts that this variant abolishes the splice donor site. This variant is considered to be pathogenic according to the ACMG guidelines. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Number of individuals with the variant: 1 Zygosity: Single Heterozygote

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	Asphyxiating thoracic dystrophy 3	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV001479572.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Publications: PubMed (1) PubMed: 29068549 Observation: 1 Collection method: research Allele origin: inherited Affected status: yes Observation 1 Collection method: research Allele origin: inherited Affected status: yes

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	short-rib polydactyly syndrome type II	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV001479722.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Publications: PubMed (1) PubMed: 29068549 Observation: 1 Collection method: research Allele origin: inherited Affected status: yes Observation 1 Collection method: research Allele origin: inherited Affected status: yes

Comment:

Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29068549, 30773290)

Comment:

This sequence change affects a donor splice site in intron 66 of the DYNC2H1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DYNC2H1 are known to be pathogenic (PMID: 23339108, 32753734, 33755199). This variant is present in population databases (no rsID available, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with short-rib polydactyly syndrome (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446536). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

This individual is heterozygous for the c.10063+2T>G variant in the DYNC2H1 gene. To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. However, this variant has been submitted as pathogenic on ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/446536/). This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.0013% (3 out of 227,450 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) predicts that this variant abolishes the splice donor site. This variant is considered to be pathogenic according to the ACMG guidelines.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
DYNC2H1 variants cause Leber congenital amaurosis without syndromic features.	Lee J	Clinical genetics	2021	PMID: 33755199
DYNC2H1 hypomorphic or retina-predominant variants cause nonsyndromic retinal degeneration.	Vig A	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32753734
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
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs1261505725 ...

These 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 Feb 15, 2026