VCV000280148.42 - ClinVar

NM_004408.4(DNM1):c.709C>T (p.Arg237Trp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004408.4(DNM1):c.709C>T (p.Arg237Trp)

Variation ID: 280148 Accession: VCV000280148.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.11 9: 128220201 (GRCh38) [ NCBI UCSC ] 9: 130982480 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 19, 2017	Oct 20, 2024	Sep 10, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004408.4:c.709C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004399.2:p.Arg237Trp	missense
NM_001005336.3:c.709C>T	NP_001005336.1:p.Arg237Trp	missense
NM_001288737.2:c.709C>T	NP_001275666.1:p.Arg237Trp	missense
NM_001288738.2:c.709C>T	NP_001275667.1:p.Arg237Trp	missense
NM_001288739.2:c.709C>T	NP_001275668.1:p.Arg237Trp	missense
NM_001374269.1:c.709C>T	NP_001361198.1:p.Arg237Trp	missense
NC_000009.12:g.128220201C>T
NC_000009.11:g.130982480C>T
NG_029726.1:g.21818C>T
	Q05193:p.Arg237Trp

... more HGVS ... less HGVS

Protein change

R237W

Other names

130982480C-T

Canonical SPDI

NC_000009.12:128220200:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA10603152 UniProtKB: Q05193#VAR_073712 OMIM: 602377.0004 dbSNP: rs760270633 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DNM1		-	-	GRCh38 GRCh37	623	913

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Developmental and epileptic encephalopathy, 31A	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 29, 2023	RCV000170498.18
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 10, 2023	RCV000263789.28
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Nov 5, 2014	RCV001265881.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 10, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000330044.9 First in ClinVar: Dec 06, 2016 Last updated: Sep 14, 2023	Comment: In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated … (more) In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27476654, 29314763, 32827528, 25262651, 26611353, 25533962, 28667181, 29186148, 33726816, 31785789, 33004838, 31440721) (less)
Pathogenic (Jul 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248837.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 4
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 31A Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893796.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Apr 15, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes Accession: SCV001334362.1 First in ClinVar: Jun 07, 2020 Last updated: Jun 07, 2020
Pathogenic (Jan 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 31A (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Pediatrics, MediClubGeorgia Accession: SCV001468641.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (3) PubMed: 25262651‚ 26611353‚ 29314763 Comment: This sequence change replaces arginine with tryptophan at codon 237 of the DNM1 protein (p.Arg237Trp). The arginine residue is highly conserved and there is a … (more) This sequence change replaces arginine with tryptophan at codon 237 of the DNM1 protein (p.Arg237Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. The variant is absent in population databases. This de novo variant has been reported in individuals affected with epileptic encephalopathy (EE) and West syndrome. It has also been reported in an individual with EE who inherited the variant from an unaffected parent (somatic mosaic). SIFT - deleterious, PolyPhen - Probably Damaging, FATHMM pred - Damaging, MutationAssessor - High, MutationTaster - diseases causing, Provean - Damaging, MetaSVM - Damaging. The parents were also tested - not detected. On Clinvar this variant is submitted as Pathogenic. (less) Clinical Features: Epileptic encephalopathy (present) , Atypical behavior (present) , Poor head control (present) , Global developmental delay (present) , Hypsarrhythmia (present) , EEG abnormality (present) , … (more) Epileptic encephalopathy (present) , Atypical behavior (present) , Poor head control (present) , Global developmental delay (present) , Hypsarrhythmia (present) , EEG abnormality (present) , Absent speech (present) , Reduced tendon reflexes (present) , Feeding difficulties (present) , Inability to walk (present) , Encephalopathy (present) , Hypotonia (present) , Horizontal nystagmus (present) , Seizure (present) , Autosomal dominant inheritance (present) , Generalized myoclonic seizure (present) , Hyporeflexia (present) , Gastroesophageal reflux (present) , Involuntary movements (present) , Difficulty walking (present) , Abnormal involuntary eye movements (present) , Feeding difficulties (present) , Chronic constipation (present) , Thrombocytopenia (present) (less) Indication for testing: Epilepsy Encephalopathy, Development Delay Age: 0-9 years Sex: female Ethnicity/Population group: Caucasian Geographic origin: Georgian Testing laboratory: 279559 Date variant was reported to submitter: 2019-10-21 Testing laboratory interpretation: Pathogenic
Pathogenic (Nov 05, 2014)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV001444053.2 First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023	Publications: PubMed (3) PubMed: 26611353‚ 28667181‚ 29427836 Number of individuals with the variant: 1 Clinical Features: Seizures (present) Sex: female Ethnicity/Population group: African American
Pathogenic (Aug 29, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Developmental and epileptic encephalopathy, 31A Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000656484.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 25262651‚ 26611353‚ 29314763 Comment: This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein … (more) This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt DNM1 protein function. ClinVar contains an entry for this variant (Variation ID: 280148). This missense change has been observed in individual(s) with epileptic encephalopathy (EE) and West syndrome (PMID: 25262651, 26611353, 29314763). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 237 of the DNM1 protein (p.Arg237Trp). (less)
Pathogenic (Mar 12, 2015)	no assertion criteria provided Method: literature only	DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 31A Affected status: not provided Allele origin: germline	OMIM Accession: SCV000222930.3 First in ClinVar: May 19, 2015 Last updated: Apr 30, 2023	Publications: PubMed (1) PubMed: 25533962 Comment on evidence: In a male patient with developmental and epileptic encephalopathy-31A (DEE31A; 616346), the Deciphering Developmental Disorders Study (2015) identified a heterozygous C-to-T transition at chromosome coordinate … (more) In a male patient with developmental and epileptic encephalopathy-31A (DEE31A; 616346), the Deciphering Developmental Disorders Study (2015) identified a heterozygous C-to-T transition at chromosome coordinate g.130,982,480 (chr9.130,982,480C-T, GRCh37) in the DNM1 gene. This missense mutation occurred as a de novo event. No functional studies were performed. (less)

Comment:

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27476654, 29314763, 32827528, 25262651, 26611353, 25533962, 28667181, 29186148, 33726816, 31785789, 33004838, 31440721)

Comment:

This sequence change replaces arginine with tryptophan at codon 237 of the DNM1 protein (p.Arg237Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. The variant is absent in population databases. This de novo variant has been reported in individuals affected with epileptic encephalopathy (EE) and West syndrome. It has also been reported in an individual with EE who inherited the variant from an unaffected parent (somatic mosaic). SIFT - deleterious, PolyPhen - Probably Damaging, FATHMM pred - Damaging, MutationAssessor - High, MutationTaster - diseases causing, Provean - Damaging, MetaSVM - Damaging. The parents were also tested - not detected. On Clinvar this variant is submitted as Pathogenic.

Comment:

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt DNM1 protein function. ClinVar contains an entry for this variant (Variation ID: 280148). This missense change has been observed in individual(s) with epileptic encephalopathy (EE) and West syndrome (PMID: 25262651, 26611353, 29314763). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 237 of the DNM1 protein (p.Arg237Trp).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
DNM1 encephalopathy - atypical phenotype with hypomyelination due to a novel de novo variant in the DNM1 gene.	Kolnikova M	Seizure	2018	PMID: 29427836
Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness.	Palmer EE	Molecular genetics & genomic medicine	2018	PMID: 29314763
DNM1 encephalopathy: A new disease of vesicle fission.	von Spiczak S	Neurology	2017	PMID: 28667181
De novo DNM1 mutations in two cases of epileptic encephalopathy.	Nakashima M	Epilepsia	2016	PMID: 26611353
Large-scale discovery of novel genetic causes of developmental disorders.	Deciphering Developmental Disorders Study	Nature	2015	PMID: 25533962
De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies.	EuroEPINOMICS-RES Consortium	American journal of human genetics	2014	PMID: 25262651

Text-mined citations for rs760270633 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_004408.4(DNM1):c.709C>T (p.Arg237Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs760270633 ...