rs797044901

Variant names:

• chr14-102002694-G-A
• rs797044901
• NM_001376.5:c.4700G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-102002694-G-A
• chr14-102002694-G-T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001376.5(DYNC1H1):​c.4700G>A​(p.Arg1567Gln) 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 (★★). ClinVar reports functional evidence for this variant: "SCV000244167: In vitro assays examining the effect of DYNC1H1 mutations on dynein microtubule motor motility demonstrated that, compared to the wild-type, the p.R1567Q alteration reduced the distance traveled by dynein–dynactin–BICD2N complexes before pausing or detaching from the microtubule (Hoang, 2017). Another functional study demonstrated that the p.R1567Q alteration reduced cytoplasmic localization of DYNC1H1 and inhibited binding interaction with dynactin 1 compared to the wild-type (Pijuan, 2021).; SCV000293268: "Published functional studies suggest a damaging effect by reducing the run length of the dyneindynactinBICD2N complexes." PMID:28196890; SCV002235597: Experimental studies have shown that this missense change affects DYNC1H1 function (PMID:28196890).; SCV005415984: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1567W) has been classified as Likely 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:9 U:1
• Conservation: PhyloP100: 9.85
• Publications: 14 publications found

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]

DYNC1H1 Gene-Disease associations (from GenCC):

• autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• intellectual disability, autosomal dominant 13

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• neuronopathy, distal hereditary motor

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease axonal type 2O

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000244167: In vitro assays examining the effect of DYNC1H1 mutations on dynein microtubule motor motility demonstrated that, compared to the wild-type, the p.R1567Q alteration reduced the distance traveled by dynein–dynactin–BICD2N complexes before pausing or detaching from the microtubule (Hoang, 2017). Another functional study demonstrated that the p.R1567Q alteration reduced cytoplasmic localization of DYNC1H1 and inhibited binding interaction with dynactin 1 compared to the wild-type (Pijuan, 2021).; SCV000293268: "Published functional studies suggest a damaging effect by reducing the run length of the dyneindynactinBICD2N complexes." PMID: 28196890; SCV002235597: Experimental studies have shown that this missense change affects DYNC1H1 function (PMID: 28196890).; SCV005415984: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-102002693-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1513471.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 14-102002694-G-A is Pathogenic according to our data. Variant chr14-102002694-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 208709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	NM_001376.5	MANE Select	c.4700G>A	p.Arg1567Gln	missense	Exon 22 of 78	NP_001367.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	ENST00000360184.10	TSL:1 MANE Select	c.4700G>A	p.Arg1567Gln	missense	Exon 22 of 78	ENSP00000348965.4	Q14204
	DYNC1H1	ENST00000681574.1		c.4700G>A	p.Arg1567Gln	missense	Exon 22 of 77	ENSP00000505523.1	A0A7P0T9C4
	DYNC1H1	ENST00000679720.1		c.4700G>A	p.Arg1567Gln	missense	Exon 22 of 78	ENSP00000505938.1	A0A7P0TA13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	1	-	Charcot-Marie-Tooth disease axonal type 2O (2)
2	-	-	Intellectual disability (2)
2	-	-	Intellectual disability, autosomal dominant 13 (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.70		Gain of disorder (P = 0.1142)
MVP		0.84
MPC		2.6
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.97
Mutation Taster		=18/82	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797044901; hg19: chr14-102469031;