rs587780564

chr14-101986017-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_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. 12/20 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. R598L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYNC1H1 NM_001376.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 U:1
• Conservation: PhyloP100: 4.62

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 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr14-101986018-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 246081.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, 0.952
• 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/exons	MANE	UniProt
DYNC1H1	NM_001376.5	c.1792C>T	p.Arg598Cys	missense_variant	8/78	ENST00000360184.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYNC1H1	ENST00000360184.10	c.1792C>T	p.Arg598Cys	missense_variant	8/78	1	NM_001376.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Département de Neurologie, Hospices Civils de Lyon	Feb 24, 2023	- -
Likely pathogenic, no assertion criteria provided	research	Center for Genetic Medicine Research, Children's National Medical Center	Jun 10, 2014	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Aug 02, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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:3 Uncertain:1

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 14, 2022	For these reasons, this variant has been classified as Pathogenic. 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: 139652). 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. This variant is not present in population databases (gnomAD no frequency). 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). -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2020	Published functional studies demonstrate a damaging effect (results in a protein that shows increased binding to the BICD2 adaptor as compared to wild type (Peeters et al., 2015); Not observed in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 31618753, 31130284, 28554554, 27549087, 26100331, 25512093, 25484024) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2015

- -

Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures;C3280220:Charcot-Marie-Tooth disease axonal type 2O;C3281202:Intellectual disability, autosomal dominant 13 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary motor and sensory neuropathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

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

Nov 20, 2013

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	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.70		Loss of MoRF binding (P = 6e-04);
MVP		0.90
MPC		2.8
ClinPred		0.99	D
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

Other links and lift over

dbSNP: rs587780564; hg19: chr14-102452354; COSMIC: COSV64143636;