rs797045177

Positions:

• chr14-101980515-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001376.5(DYNC1H1):​c.926G>A​(p.Arg309His) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYNC1H1 NM_001376.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.48

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.924
• PP5: Variant 14-101980515-G-A is Pathogenic according to our data. Variant chr14-101980515-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 209107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101980515-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYNC1H1	NM_001376.5	c.926G>A	p.Arg309His	missense_variant	5/78	ENST00000360184.10	NP_001367.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.926G>A	p.Arg309His	missense_variant	5/78	1	NM_001376.5	ENSP00000348965	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with DYNC1H1-related conditions (PMID: 29671837). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 209107). 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. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 309 of the DYNC1H1 protein (p.Arg309His). This variant is not present in population databases (gnomAD no frequency). -

Lissencephaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

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- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2016

The R309H variant has been previously reported as a de novo potentially causal germline variant in an individual with brain malformations on MRI, including posterior-predominant pachygyria, corpus callosum abnormalities, small anterior vermis and short pons (Jamuar et al., 2014). R309H 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 in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R309H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Based on the currently available information, GeneDx interprets R309H as a likely pathogenic variant; however, the possibility that it is benign cannot be excluded. -

Intellectual disability, autosomal dominant 13 Pathogenic:1

Pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

May 19, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.57		Loss of catalytic residue at R309 (P = 0.0069);
MVP		0.83
MPC		2.6
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.86
gMVP		0.99

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: rs797045177; hg19: chr14-102446852;