rs587780564

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.1792C>T(p.Arg598Cys) variant causes a missense change. 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

DYNC1H1
NM_001376.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:1

Conservation

PhyloP100: 4.62

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 DYNC1I2 (size 255) 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, 0.952

PP5

Variant 14-101986017-C-T is Pathogenic according to our data. Variant chr14-101986017-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 139652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101986017-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.1792C>T	p.Arg598Cys	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.1792C>T	p.Arg598Cys	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/Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures

Pathogenic:4

Aug 02, 2019

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 24, 2023

Département de Neurologie, Hospices Civils de Lyon

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 10, 2014

Center for Genetic Medicine Research, Children's National Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with spinal muscular atrophy, lower extremity-predominant 1 (MIM#158600), intellectual disability (MIM#614563) and Charcot-Marie-Tooth disease, axonal, type 20 (MIM#614228). While there is no clear genotype-phenotype correlation, there is some association between the severity of the variant on protein function and the phenotype that is manifested (PMID: 25512093, PMID: 28196890). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 25512093). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic. It has been shown to segregate within families, and arise de novo, in individuals with spinal muscular atrophy or spinal muscular atrophy with lower extremity predominant (ClinVar, PMID: 25512093, PMID: 28554554). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional analysis of patient lymphoblasts indicated an increased binding in adaptor protein BICD2 (PMID: 25512093). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Charcot-Marie-Tooth disease axonal type 2O

Pathogenic:3Uncertain:1

Jul 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 DYNC1H1 protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 139652). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 598 of the DYNC1H1 protein (p.Arg598Cys). 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 (SMALED) (PMID: 25484024, 25497877, 25512093, 27549087, 28554554). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as Likely Pathogenic, for Charcot-Marie-Tooth disease axonal type 20, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/25512093). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. -

not provided

Pathogenic:2

May 01, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (results in a protein that shows increased binding to the BICD2 adaptor as compared to wild type) (PMID: 25512093); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28554554, 25484024, 25512093, 26100331, 27549087, 36720598, 37337091, 35899263, 34535505, 35468861, 25497877, 37470033, 31618753, 31130284, 33060286, 34758253, 25609763) -

Inborn genetic diseases

Pathogenic:1

Oct 28, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary motor and sensory neuropathy

Pathogenic:1

Nov 20, 2013

Molecular Neurogenomics lab, VIB Department of Molecular Genetics; University of Antwerp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

segregates with the phenotype; absent in 179 ethnically matched controls -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.14

MutationAssessor

Pathogenic

3.2

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.70

Loss of MoRF binding (P = 6e-04);

MVP

0.90

MPC

2.8

ClinPred

0.99

GERP RS

5.8

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.89

gMVP

0.98

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