rs863223953

chr12-32731362-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_001278464.2(DNM1L):c.1246C>T(p.Arg416Cys) 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. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNM1L NM_001278464.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 3.93

Genes affected

DNM1L (HGNC:2973): (dynamin 1 like) This gene encodes a member of the dynamin superfamily of GTPases. The encoded protein mediates mitochondrial and peroxisomal division, and is involved in developmentally regulated apoptosis and programmed necrosis. Dysfunction of this gene is implicated in several neurological disorders, including Alzheimer's disease. Mutations in this gene are associated with the autosomal dominant disorder, encephalopathy, lethal, due to defective mitochondrial and peroxisomal fission (EMPF). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2013]

YARS2 (HGNC:24249): (tyrosyl-tRNA synthetase 2) This gene encodes a mitochondrial protein that catalyzes the attachment of tyrosine to tRNA(Tyr). Mutations in this gene are associated with myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2). [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001278464.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DNM1L
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• PP5: Variant 12-32731362-C-T is Pathogenic according to our data. Variant chr12-32731362-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 214313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32731362-C-T is described in Lovd as [Pathogenic]. Variant chr12-32731362-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNM1L	NM_001278464.2	c.1246C>T	p.Arg416Cys	missense_variant	12/21	ENST00000553257.6
DNM1L	NM_012062.5	c.1207C>T	p.Arg403Cys	missense_variant	11/20	ENST00000549701.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNM1L	ENST00000553257.6	c.1246C>T	p.Arg416Cys	missense_variant	12/21	2	NM_001278464.2
DNM1L	ENST00000549701.6	c.1207C>T	p.Arg403Cys	missense_variant	11/20	1	NM_012062.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Pathogenic:8

Pathogenic, criteria provided, single submitter	research	Cavalleri Lab, Royal College of Surgeons in Ireland	Mar 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The DNM1L c.1207C>T variant has been previously reported as disease-causing heterozygous de novo variant in multiple patients affected with Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (Fahrner et al., 2016; Schmid et. al., 2019; McCormack et. al., 2020). The p.Arg403Cys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Arg403Cys in DNM1L is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. In silico analysis supports that this missense variant has a deleterious effect on protein structure/function. The amino acid Arg at position 403 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Apr 01, 2022	0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with encephalopathy due to defective mitochondrial peroxisomal fission 1 (EMPF1; MIM#614388) and optic atrophy 5 (MIM#610708). Missense variants with a dominant negative mechanism has been mostly reported in individuals with dominant EMPF1, with optic atrophy less common. Loss of functional null and missense variants have been reported in individuals with recessive EMPF1 (OMIM, PMID: 29529134). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM, PMID: 29529134). (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 many times as pathogenic, and observed in multiple de novo individuals with initially normal development, followed by mitochondrial encephalopathy, refractory status epilepticus and/or global developmental delay (ClinVar, PMID: 30939602). (SP) 1207 - Parental origin of the variant is unresolved. Testing of this individual's mother has proven the variant was not maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 26, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Department, Xiangya Hospital, Central South University	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 10, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect DNM1L protein function (PMID: 27145208, 29877124). This variant has been observed to be de novo in individuals affected with DNM1L-related conditions (PMID: 27145208, 29877124). ClinVar contains an entry for this variant (Variation ID: 214313). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 403 of the DNM1L protein (p.Arg403Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27145208, 30711678, 30939602, 29877124, 28969390, 30801875, 30109270, 30767894, 30085106, 31216405) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2017

- -

Optic atrophy 5;C3280660:Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	35
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.5	H;.;.;H;.;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.6	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;.;D;.;.;.;.
Vest4		0.83
MutPred		0.62		Gain of catalytic residue at P402 (P = 0);.;.;Gain of catalytic residue at P402 (P = 0);.;Gain of catalytic residue at P402 (P = 0);Gain of catalytic residue at P402 (P = 0);.;
MVP		0.93
MPC		2.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863223953; hg19: chr12-32884296; COSMIC: COSV56773662; COSMIC: COSV56773662;