rs387906738

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_001376.5(DYNC1H1):c.917A>G(p.His306Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

DYNC1H1
NM_001376.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:2O:1

Conservation

PhyloP100: 8.84

Publications

20 publications found

Variant links:

Genes affected

DYNC1H1 (HGNC:2961): (dynein cytoplasmic 1 heavy chain 1) Dyneins are a group of microtubule-activated ATPases that function as molecular motors. They are divided into two subgroups of axonemal and cytoplasmic dyneins. The cytoplasmic dyneins function in intracellular motility, including retrograde axonal transport, protein sorting, organelle movement, and spindle dynamics. Molecules of conventional cytoplasmic dynein are comprised of 2 heavy chain polypeptides and a number of intermediate and light chains.This gene encodes a member of the cytoplasmic dynein heavy chain family. [provided by RefSeq, Oct 2008]

DYNC1H1 Gene-Disease associations (from GenCC):

autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
intellectual disability, autosomal dominant 13
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
neuronopathy, distal hereditary motor
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease axonal type 2O
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DYNC1H1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001376.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-101980506-A-G is Pathogenic according to our data. Variant chr14-101980506-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1H1	NM_001376.5 link	c.917A>G	p.His306Arg	missense_variant	Exon 5 of 78	ENST00000360184.10	NP_001367.2	Q14204

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10 link	c.917A>G	p.His306Arg	missense_variant	Exon 5 of 78	1	NM_001376.5	ENSP00000348965.4		Q14204

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2O

Pathogenic:3Uncertain:1

Nov 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 306 of the DYNC1H1 protein (p.His306Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 21820100). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30029). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYNC1H1 protein function. Experimental studies have shown that this missense change affects DYNC1H1 function (PMID: 29379136). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Sep 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 29, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease

Uncertain:1Other:1

Inherited Neuropathy Consortium

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 30, 2015

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures

Pathogenic:1

Nov 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.3

PhyloP100

8.8

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.38

Sift

Benign

0.17

Polyphen

0.055

Vest4

0.81

MutPred

0.55

Gain of MoRF binding (P = 0.0348);

MVP

0.89

MPC

1.6

ClinPred

0.89

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.72

gMVP

0.97

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over