rs1327664377

Variant names:

• chr14-102001671-C-T
• rs1327664377
• NM_001376.5:c.4532C>T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001376.5(DYNC1H1):​c.4532C>T​(p.Pro1511Leu) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P1511P) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC1H1 NM_001376.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.75

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 15 ACMG points.

• 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, 0.949
• PP5: Variant 14-102001671-C-T is Pathogenic according to our data. Variant chr14-102001671-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 472535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1H1	NM_001376.5	c.4532C>T	p.Pro1511Leu	missense_variant	Exon 21 of 78	ENST00000360184.10	NP_001367.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.4532C>T	p.Pro1511Leu	missense_variant	Exon 21 of 78	1	NM_001376.5	ENSP00000348965.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

May 01, 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 1511 of the DYNC1H1 protein (p.Pro1511Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DYNC1H1-related disorders (PMID: 32656949). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 472535). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Progressive muscle weakness Pathogenic:1

Feb 06, 2020

Pediatric Genomics Discovery Program, Yale University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The p.Pro1511Leu variant in DYNC1H1 has not been reported prior to this entry, and is absent from controls (PM2). It was identified to be de novo (PS2) in a patient with progressive muscular weakness and atrophy affecting the upper and lower extremities, extraocular muscles, and vocal cords. She has progressive contractures and restrictive pulmonary disease from severe scoliosis. Her most recent EMG shows severe chronic pure motor neuropathy/neuronopathy. This residue is highly conserved in species. Multiple lines of in silico predictors suggest damaging effect of this amino acid substitution (PP3). DYNC1H1 is a gene with a low rate of benign missense change, whereas most pathogenic variants in this gene are missense (PP2). The p.Pro1511Leu variant is located in the stem domain which is where dimerization occurs; other variants in this domain have been associated with lower-extremity predominant spinal muscular atrophy (PM1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-9.6	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.67		Loss of ubiquitination at K1508 (P = 0.0795);
MVP		0.86
MPC		2.4
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1327664377; hg19: chr14-102468008; COSMIC: COSV64134818;