rs121909092

Variant names:

• chr19-10793829-G-A
• rs121909092
• NM_001005361.3:c.1102G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-10793829-G-A
• chr19-10793829-G-C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3_Moderate PM2_Supporting PS4 PP2 PP3 PS2

This summary comes from the ClinGen Evidence Repository: The NM_001005361.3:c.1102G>A variant in DNM2 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 368 (p.Glu368Lys). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.799, which is above the threshold of 0.7, evidence that correlates with impact to DNM2 function (PP3). 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). This variant has been reported in at least 6 probands with centronuclear myopathy (PS4; PMIDs: 16227997, 22613877, 25501959, 27159402, 33124102). Of those 6 individuals, the variant was identified as a de novo occurrence with confirmed parental relationships in at least 3 of those individuals with centronuclear myopathy (PS2_VeryStrong; PMIDs: 16227997, 27159402, 33124102). Oligomerization in Sf9 cells showed defective autoinhibition of self-assembly, indicating that this variant impacts protein function (PMID:26199319). Additionally, GTPase activity in Sf9 cells was between 2–2.5-fold higher than wild-type DNM2 (PS3_Moderate). 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: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP2, PP3. (ClinGen Congenital Myopathies VCEP Specifications Version 1.0; 10/25/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA118661/MONDO:0018947/148

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNM2 NM_001005361.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13 U:1
• Conservation: PhyloP100: 10.0
• Publications: 29 publications found

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]

DNM2 Gene-Disease associations (from GenCC):

• autosomal dominant centronuclear myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease dominant intermediate B

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• autosomal dominant Charcot-Marie-Tooth disease type 2M

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fetal akinesia-cerebral and retinal hemorrhage syndrome

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary spastic paraplegia

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNM2	NM_001005361.3	c.1102G>A	p.Glu368Lys	missense_variant	Exon 8 of 21	ENST00000389253.9	NP_001005361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNM2	ENST00000389253.9	c.1102G>A	p.Glu368Lys	missense_variant	Exon 8 of 21	5	NM_001005361.3	ENSP00000373905.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251474 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000999 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal dominant centronuclear myopathy Pathogenic:4

-

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007282 / PMID: 16227997 / 3billion dataset). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 25501959, 26273216). A different missense change at the same codon (p.Glu368Gln) has been reported to be associated with DNM2 related disorder (PMID: 17825552). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 06, 2023

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was previously reported in individuals affected with autosomal dominant centronuclear myopathy and considered one of the most common mutations causing the disorder and has been shown to arise de novo in numerous affected individuals [PMID: 22613877, 25501959, 25262827, 20927630, 22396310, 23338057, 20227276, 25957634, 26273216, 21221624, 23394783 16227997]. Functional studies have shown that it causes an increase in GTPase activity of the protein along and formation of oligomers that are resistant to disassembly and have a dominant negative effect on protein function [PMID: 20529869, 26199319, 21762456]. -

not provided Pathogenic:3

Dec 28, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 14, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that p.(E368K) results in increased GTPase activity, which stabilizes the dynamin complex, rendering it resistant to normal disassembly (Wang et al., 2010; Chin et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25501959, 32403337, 21221624, 26199319, 20227276, 20529869, 17008356, 21762456, 25262827, 23338057, 23394783, 26273216, 25127990, 24465259, 22613877, 33124102, 19130742, 33333461, 34463354, 22396310, 16227997) -

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

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 368 of the DNM2 protein (p.Glu368Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant centronuclear myopathy (PMID: 16227997, 17008356, 19130742, 20227276, 20927630, 21221624, 22396310, 22613877, 23338057, 23394783, 24465259, 25262827, 25501959, 25957634, 26273216). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7282). Invitae Evidence 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 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, 21762456, 26199319). For these reasons, this variant has been classified as Pathogenic. -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: literature only

- -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Centronuclear myopathy Pathogenic:2

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2024

ClinGen Congenital Myopathies Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001005361.3:c.1102G>A variant in DNM2 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 368 (p.Glu368Lys). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.799, which is above the threshold of 0.7, evidence that correlates with impact to DNM2 function (PP3). 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). This variant has been reported in at least 6 probands with centronuclear myopathy (PS4; PMIDs: 16227997, 22613877, 25501959, 27159402, 33124102). Of those 6 individuals, the variant was identified as a de novo occurrence with confirmed parental relationships in at least 3 of those individuals with centronuclear myopathy (PS2_VeryStrong; PMIDs: 16227997, 27159402, 33124102). Oligomerization in Sf9 cells showed defective autoinhibition of self-assembly, indicating that this variant impacts protein function (PMID: 26199319). Additionally, GTPase activity in Sf9 cells was between 2–2.5-fold higher than wild-type DNM2 (PS3_Moderate). 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: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP2, PP3. (ClinGen Congenital Myopathies VCEP Specifications Version 1.0; 10/25/2024) -

Myopathy Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DNM2-related disorder Pathogenic:1

Jan 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DNM2 c.1102G>A variant is predicted to result in the amino acid substitution p.Glu368Lys. This variant has been reported in many unrelated individuals with autosomal dominant centronuclear myopathy (see example: Bitoun et al. 2005. PMID: 16227997; Mori-Yoshimura et al. 2012. PubMed ID: 22613877; Reumers. 2021. PubMed ID: 34463354). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	.;.;.;D;.;D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;M;.
PhyloP100		10
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.6	.;D;D;D;D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	.;D;D;D;D;.
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		0.17, 0.40	.;B;.;B;.;.
Vest4		0.96
MutPred		0.89		Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);.;
MVP		0.96
MPC		2.0
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.85
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909092; hg19: chr19-10904505;