chr14-101986552-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_001376.5(DYNC1H1):c.2327C>T(p.Pro776Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

DYNC1H1
NM_001376.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.56

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a region_of_interest Interaction with DYNC1LI2 (size 151) in uniprot entity DYHC1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001376.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the DYNC1H1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 122 curated pathogenic missense variants (we use a threshold of 10). The gene has 287 curated benign missense variants. Gene score misZ: 10.967 (above the threshold of 3.09). Trascript score misZ: 16.053 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant non-syndromic intellectual disability, neuronopathy, distal hereditary motor, intellectual disability, autosomal dominant 13, autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures, Charcot-Marie-Tooth disease axonal type 2O.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

PP5

Variant 14-101986552-C-T is Pathogenic according to our data. Variant chr14-101986552-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 372934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101986552-C-T is described in Lovd as [Pathogenic]. Variant chr14-101986552-C-T is described in Lovd as [Likely_pathogenic]. Variant chr14-101986552-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1H1	NM_001376.5 link	c.2327C>T	p.Pro776Leu	missense_variant	Exon 8 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.2327C>T	p.Pro776Leu	missense_variant	Exon 8 of 78	1	NM_001376.5	ENSP00000348965.4		Q14204

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures

Pathogenic:4

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372934). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26846447). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 16, 2018

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2327C>T variant in the DYNC1H1 gene has been reported previously (PMCID:4742772). The patient and his 2 similarly affected identical twin brothers were found to carry the variant. The father was mosaic for this variant with mild symptoms. -

Feb 24, 2023

Département de Neurologie, Hospices Civils de Lyon

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PP2, PP3, PM1, PM2, PS4_Moderate -

not provided

Pathogenic:4

Jul 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31607746, 26846447, 28554554, 32703465, 26100331, 25609763, 25512093, 35899263, 33060286) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DYNC1H1: PS2:Very Strong, PM2, PS4:Moderate, PP2 -

Nov 28, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2O

Pathogenic:1

Nov 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 776 of the DYNC1H1 protein (p.Pro776Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with lower extremity predominant spinal muscular atrophy (PMID: 26846447, 28554554). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 372934). 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. -

Charcot-Marie-Tooth disease axonal type 2O;C3281202:Intellectual disability, autosomal dominant 13;C5780022:Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP4+PP1_Strong+PM6_Strong+PS4_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.079

MutationAssessor

Pathogenic

3.3

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-9.0

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

Polyphen

1.0

Vest4

0.94

MutPred

0.55

Gain of catalytic residue at P776 (P = 0.0521);

MVP

0.89

MPC

2.4

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.97

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over