rs121909090

Positions:

• chr19-10793832-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS4 PP1_Strong PS3_Supporting PM6 PM5 PP2 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1105C>T variant in DNM2 is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 369 (p.Arg369Trp). The highest population minor allele frequency in gnomAD v4.1 is 0.00001335 (1/74912 alleles) in the African/African American population, which is lower than the ClinGen Congenital Myopathies VCEP threshold for PM2_Supporting, meeting this criterion (PM2_Supporting). DNM2, in which the variant was identified, is defined by the ClinGen Congenital Myopathies VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). The computational predictor REVEL gives a score of 0.683, which is neither above nor below the thresholds predicting a damaging or benign impact on RYR1 function. This variant has been reported in at least 11 probands from 6 families meeting phenotypic criteria distal muscular weakness and ptosis, which is highly specific for centronuclear myopathy (PS4; PMIDs: 16227997, 20817456, 22613877, 25492887, 25501959, 28676641). The variant has been reported to segregate with centronuclear myopathy in 5 affected family members from 2 families (PP1_Strong; PMIDs: 16227997, 22613877). Two different missense variants (c.1106G>T, p.Arg369Leu; p.Arg369Gln, c.1106G>A) in the same codon have been classified as likely pathogenic and pathogenic, respectively, for autosomal dominant centronuclear myopathy by the ClinGen Congenital Myopathies VCEP (and autosomal dominant Charcot-Marie-Tooth disease by the ClinGen Charcot-Marie-Tooth disease VCEP) (PM5). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with centronuclear myopathy (PM6; PMIDs: 16227997). A cell culture of human myoblasts from quadriceps showed impaired actin development, indicating that this variant impacts protein function (PMID:28676641; PS3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant centronuclear myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PS4, PP1_Strong, PM5, PM6, PM2_Supporting, PP2, PS3_Supporting. (ClinGen Congenital Myopathies VCEP specifications version 1; 8/7/24) LINK:https://erepo.genome.network/evrepo/ui/classification/CA118658/MONDO:0018947/148

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1
• Conservation: PhyloP100: 0.554

Genes affected

DNM2 (HGNC:2974): (dynamin 2) Dynamins represent one of the subfamilies of GTP-binding proteins. These proteins share considerable sequence similarity over the N-terminal portion of the molecule, which contains the GTPase domain. Dynamins are associated with microtubules. They have been implicated in cell processes such as endocytosis and cell motility, and in alterations of the membrane that accompany certain activities such as bone resorption by osteoclasts. Dynamins bind many proteins that bind actin and other cytoskeletal proteins. Dynamins can also self-assemble, a process that stimulates GTPase activity. Five alternatively spliced transcripts encoding different proteins have been described. Additional alternatively spliced transcripts may exist, but their full-length nature has not been determined. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM2	NM_001005361.3	c.1105C>T	p.Arg369Trp	missense_variant	8/21	ENST00000389253.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM2	ENST00000389253.9	c.1105C>T	p.Arg369Trp	missense_variant	8/21	5	NM_001005361.3	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease dominant intermediate B Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 369 of the DNM2 protein (p.Arg369Trp). This variant is present in population databases (rs121909090, gnomAD 0.01%). This missense change has been observed in individual(s) with DNM2-related conditions (PMID: 16227997, 20817456, 22613877, 25492887). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7280). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DNM2 protein function. Experimental studies have shown that this missense change affects DNM2 function (PMID: 20529869, 24016602, 28676641). This variant disrupts the p.Arg369 amino acid residue in DNM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16227997, 25501959). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

Autosomal dominant centronuclear myopathy Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 28, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2021	Segregates with centronuclear myopathy in multiple individuals from several unrelated families in published literature (Bitoun et al., 2005; Hanna et al., 2013; Mori-Yoshimura et al.,2012); Published functional studies demonstrate that R369W enhances the protein's ability to make strong dynamin complexes that are resistant to being broken down (Wang et al., 2010; James et al., 2014); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22924779, 22613877, 24016602, 25492887, 20529869, 20817456, 16227997, 25501959, 32403337, 32528171, 33187981) -

Charcot-Marie-Tooth disease Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Inherited Neuropathy Consortium

-

- -

Centronuclear myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	.;.;.;D;.;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.6	M;M;M;M;M;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.3	.;D;D;D;D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0030	.;D;D;D;D;.
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D;.;.
Vest4		0.90
MutPred		0.91		Loss of methylation at R369 (P = 0.0439);Loss of methylation at R369 (P = 0.0439);Loss of methylation at R369 (P = 0.0439);Loss of methylation at R369 (P = 0.0439);Loss of methylation at R369 (P = 0.0439);.;
MVP		0.94
MPC		2.2
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.89

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: rs121909090; hg19: chr19-10904508;