rs863223953
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_012062.5(DNM1L):c.1207C>T(p.Arg403Cys) 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_012062.5 missense
NM_012062.5 missense
Scores
16
2
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
In a region_of_interest Middle domain (size 145) in uniprot entity DNM1L_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_012062.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNM1L. . Gene score misZ: 3.8282 (greater than the threshold 3.09). Trascript score misZ: 5.3198 (greater than threshold 3.09). The gene has 31 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. GenCC has associacion of the gene with encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, encephalopathy due to mitochondrial and peroxisomal fission defect, optic atrophy 5, Leigh syndrome, autosomal dominant optic atrophy, classic form.
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
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| DNM1L | ENST00000553257.6 | c.1246C>T | p.Arg416Cys | missense_variant | 12/21 | 2 | NM_001278464.2 | ENSP00000449089.1 | ||
| DNM1L | ENST00000549701.6 | c.1207C>T | p.Arg403Cys | missense_variant | 11/20 | 1 | NM_012062.5 | ENSP00000450399.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 30, 2023 | - - |
| 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 | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Mar 31, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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 | Mendelics | May 28, 2019 | - - |
| 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 | literature only | OMIM | Aug 25, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Pediatric Department, Xiangya Hospital, Central South University | - | - - |
not provided Pathogenic:4
| 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) - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;.;D;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.;H;.;H;H;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;D;.;.;.;.
Vest4
MutPred
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
MPC
2.6
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 24
Find out detailed SpliceAI scores and Pangolin per-transcript scores at