VCV000374190.16 - ClinVar

NM_001376.5(DYNC1H1):c.6994C>T (p.Arg2332Cys)

Germline

Classification

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

Pathogenic/Likely pathogenic
Pathogenic (5); Likely pathogenic (2)

7 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_001376.5(DYNC1H1):c.6994C>T (p.Arg2332Cys)

Variation ID: 374190 Accession: VCV000374190.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q32.31 14: 102012450 (GRCh38) [ NCBI UCSC ] 14: 102478787 (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	Jan 13, 2017	Apr 25, 2026	Feb 1, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_001376.5:c.6994C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001367.2:p.Arg2332Cys	missense
NC_000014.9:g.102012450C>T
NC_000014.8:g.102478787C>T
NG_008777.1:g.52923C>T

Protein change

R2332C

Other names

Canonical SPDI

NC_000014.9:102012449:C:T

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.

Links

ClinGen: CA16043479 dbSNP: rs1057518961 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.
DYNC1H1		No evidence available	No evidence available	GRCh38 GRCh37	5391	5682

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.
Delayed gross motor development Delayed speech and language development Global developmental delay Microcephaly Seizure	Likely pathogenic (1)	criteria provided, single submitter	Jun 6, 2014	RCV000414777.2
Charcot-Marie-Tooth disease axonal type 2O	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 7, 2024	RCV001198404.8
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Aug 19, 2019	RCV001267559.3
Intellectual disability, autosomal dominant 13	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 12, 2024	RCV003223402.3
not provided	Pathogenic (1)	criteria provided, single submitter	Feb 1, 2026	RCV006650103.1

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.
Likely pathogenic (Jun 06, 2014) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Delayed gross motor development Delayed speech and language development Global developmental delay Microcephaly Seizure	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000493024.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Likely pathogenic (Jan 01, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Charcot-Marie-Tooth disease axonal type 2O	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369331.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: show This variant was classified as: Likely pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Pathogenic (Apr 20, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Intellectual disability, autosomal dominant 13	Duke University Health System Sequencing Clinic, Duke University Health System Accession: SCV003919013.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Publications: PubMed (1) PubMed: 25590979 Observation: 1 Collection method: research Allele origin: de novo Affected status: yes Observation 1 Collection method: research Allele origin: de novo Affected status: yes

Pathogenic (Dec 12, 2024) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Intellectual disability, autosomal dominant 13	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005883666.1 First in ClinVar: Mar 16, 2025 Last updated: Mar 16, 2025	Publications: PubMed (2) PubMed: 25590979‚ 36175372 Comment: show Variant summary: DYNC1H1 c.6994C>T (p.Arg2332Cys) results in a non-conservative amino acid change located in the P-loop containing nucleoside triphosphate hydrolases (IPR027417) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant was absent in gnomAD V4. c.6994C>T has been reported in the literature as a de novo occurrence in multiple individuals affected with Intellectual disability, autosomal dominant 13 (examples: Zhu_2015, Liu_2022, Internal data). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36175372, 25590979). ClinVar contains an entry for this variant (Variation ID: 374190). Based on the evidence outlined above, the variant was 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 (Aug 19, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Ambry exome assertion method (8-5-2015))	Inborn genetic diseases	Ambry Genetics Accession: SCV001445740.3 First in ClinVar: Nov 21, 2020 Last updated: Apr 13, 2025	Publications: PubMed (3) PubMed: 25590979‚ 27754416‚ 29286531 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) , Microcephaly (present) , Colpocephaly (present) , Cortical cataract (present) , Heart murmur (present) , Constipation (present) , Failure to thrive (present) Sex: female Ethnicity/Population group: African American

Pathogenic (Nov 07, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Charcot-Marie-Tooth disease axonal type 2O	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003442718.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 15, 2026	Publications: PubMed (3) PubMed: 25590979‚ 27754416‚ 29286531 Comment: show This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2332 of the DYNC1H1 protein (p.Arg2332Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant intellectual disability (PMID: 25590979, 27754416, 29286531). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 374190). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DYNC1H1 protein function with a positive predictive value of 95%. 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 (Feb 01, 2026) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV007547786.1 First in ClinVar: Apr 25, 2026 Last updated: Apr 25, 2026	Comment: show DYNC1H1: PS2, PM2, PS4:Moderate, PP2, PP3 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Uncertain significance (Jan 06, 2016) N Not contributing to aggregate classification	no assertion criteria provided	Charcot-Marie-Tooth disease axonal type 2O	Inherited Neuropathy Consortium Ii, University Of Miami Accession: SCV004174362.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023	Publications: PubMed (1) PubMed: 25590979 Observation: 1 Collection method: literature only Allele origin: germline Affected status: yes Observation 1 Collection method: literature only Allele origin: germline Affected status: yes

Comment:

Variant summary: DYNC1H1 c.6994C>T (p.Arg2332Cys) results in a non-conservative amino acid change located in the P-loop containing nucleoside triphosphate hydrolases (IPR027417) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant was absent in gnomAD V4. c.6994C>T has been reported in the literature as a de novo occurrence in multiple individuals affected with Intellectual disability, autosomal dominant 13 (examples: Zhu_2015, Liu_2022, Internal data). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36175372, 25590979). ClinVar contains an entry for this variant (Variation ID: 374190). 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 2332 of the DYNC1H1 protein (p.Arg2332Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant intellectual disability (PMID: 25590979, 27754416, 29286531). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 374190). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DYNC1H1 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

Title	Author	Journal	Year	Link
DYNC1H1-related epilepsy: Genotype-phenotype correlation.	Liu W	Developmental medicine and child neurology	2023	PMID: 36175372
Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice.	Tumienė B	Clinical genetics	2018	PMID: 29286531
Congenital Cataracts and Gut Dysmotility in a DYNC1H1 Dyneinopathy Patient.	Gelineau-Morel R	Genes	2016	PMID: 27754416
Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.	Zhu X	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25590979

Text-mined citations for rs1057518961 ...

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 Apr 26, 2026