rs1057518287

Positions:

• chr14-102008245-G-A
• chr14-102008245-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001376.5(DYNC1H1):​c.5885G>A​(p.Arg1962His) 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. 14/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1962L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC1H1 NM_001376.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001376.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-102008244-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 245597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DYNC1H1. . Gene score misZ 10.967 (greater than the threshold 3.09). Trascript score misZ 16.053 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.921
• PP5: Variant 14-102008245-G-A is Pathogenic according to our data. Variant chr14-102008245-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 373213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC1H1	NM_001376.5	c.5885G>A	p.Arg1962His	missense_variant	29/78	ENST00000360184.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.5885G>A	p.Arg1962His	missense_variant	29/78	1	NM_001376.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 25, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2016	The R1962H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species, and different missense variants in the same residue (R1962C, R1962L) have been reported in the Human Gene Mutation Database in association with DYNC1H1-related disorders (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R1962H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2018

The p.R1962H variant (also known as c.5885G>A), located in coding exon 29 of the DYNC1H1 gene, results from a G to A substitution at nucleotide position 5885. The arginine at codon 1962 is replaced by histidine, an amino acid with highly similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of DYNC1H1-related neurological disorder (Ambry internal data). Internal structural analysis indicates this variant to be disruptive to ATP binding (Ambry internal data; Zhang K et al. Cell, 2017 Jun;169:1303-1314.e18). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Charcot-Marie-Tooth disease axonal type 2O Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2023

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. ClinVar contains an entry for this variant (Variation ID: 373213). This missense change has been observed in individual(s) with clinical features of DYNC1H1-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1962 of the DYNC1H1 protein (p.Arg1962His). This variant disrupts the p.Arg1962 amino acid residue in DYNC1H1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23603762, 28196890, 29314763). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.41		Loss of helix (P = 0.1299);
MVP		0.82
MPC		2.6
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.92
gMVP		1.0

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

Other links and lift over

dbSNP: rs1057518287; hg19: chr14-102474582;