rs713993043

chr14-101980380-G-Achr14-101980380-G-Cchr14-101980380-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_001376.5(DYNC1H1):c.791G>A(p.Arg264Gln) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYNC1H1 NM_001376.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:4
• Conservation: PhyloP100: 9.57

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-101980380-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1685305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, DYNC1H1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant 14-101980380-G-A is Pathogenic according to our data. Variant chr14-101980380-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210883.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYNC1H1	NM_001376.5	c.791G>A	p.Arg264Gln	missense_variant	5/78	ENST00000360184.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.791G>A	p.Arg264Gln	missense_variant	5/78	1	NM_001376.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2022	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: 25609763, 26100331, 25512093, 32656949) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2018	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 10, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg264 amino acid residue in DYNC1H1. Other variant(s) that disrupt this residue have been observed in individuals with DYNC1H1-related conditions (PMID: 25512093), which suggests that this may be a clinically significant amino acid residue. 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: 210883). This missense change has been observed in individual(s) with spinal muscular atrophy (PMID: 25609763). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 264 of the DYNC1H1 protein (p.Arg264Gln). -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

Neurodevelopmental delay Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

DYNC1H1-related neurological disorders Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 24, 2023

The DYNC1H1 c.791G>A, p.(Arg264Gln) missense variant has been identified in an individual with a phenotype consistent with DYNC1H1-related neurological disorders who demonstrated lower limb malformations, compromised hand function, fine motor difficulties and a brain malformation resembling polymicrogyria by MRI (Scoto et al. 2015). Additionally, a different amino acid substitution at the same codon, p.(Arg264Leu), has been reported in an individual with a phenotype consistent with DYNC1H1-related neurological disorders (Peeters et al. 2015). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest this variant may impact the gene or gene product. The variant was identified in a de novo state in the proband. Based on the available evidence, the c.791G>A, p.(Arg264Gln) variant is classified as likely pathogenic for DYNC1H1-related neurological disorders. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 08, 2015

- -

Neuronopathy, distal hereditary motor, autosomal dominant Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.51		Loss of MoRF binding (P = 0.0399);
MVP		0.72
MPC		2.4
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.56
gMVP		0.93

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: rs713993043; hg19: chr14-102446717;