NM_004408.4(DNM1):c.709C>T (p.Arg237Trp) AND Developmental and epileptic encephalopathy, 31A

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Aug 29, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000170498.17

Allele description

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

Gene:

DNM1:dynamin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.11

Genomic location:

Preferred name:

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

HGVS:

NC_000009.12:g.128220201C>T
NG_029726.1:g.21818C>T
NM_001005336.3:c.709C>T
NM_001288737.2:c.709C>T
NM_001288738.2:c.709C>T
NM_001288739.2:c.709C>T
NM_001374269.1:c.709C>T
NM_004408.4:c.709C>TMANE SELECT
NP_001005336.1:p.Arg237Trp
NP_001275666.1:p.Arg237Trp
NP_001275667.1:p.Arg237Trp
NP_001275668.1:p.Arg237Trp
NP_001361198.1:p.Arg237Trp
NP_004399.2:p.Arg237Trp
NC_000009.11:g.130982480C>T
NM_004408.2:c.709C>T
NM_004408.3:c.709C>T
Q05193:p.Arg237Trp

Nucleotide change:

130982480C-T

Protein change:

R237W

Links:

UniProtKB: Q05193#VAR_073712; OMIM: 602377.0004; dbSNP: rs760270633

NCBI 1000 Genomes Browser:

rs760270633

Molecular consequence:

NM_001005336.3:c.709C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001288737.2:c.709C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001288738.2:c.709C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001288739.2:c.709C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001374269.1:c.709C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004408.4:c.709C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Developmental and epileptic encephalopathy, 31A
Synonyms:: Epileptic encephalopathy, early infantile, 31; Developmental and epileptic encephalopathy, 31
Identifiers:: MONDO: MONDO:0014598; MedGen: C4225357; Orphanet: 2382; OMIM: 616346

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000222930	OMIM	no assertion criteria provided	Pathogenic (Mar 12, 2015)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000656484	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 29, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25262651, 26611353, 29314763, 28492532
SCV000893796	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001468641	Pediatrics, MediClubGeorgia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2021)	de novo	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25262651, 26611353, 29314763, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Caucasian	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Large-scale discovery of novel genetic causes of developmental disorders.

Deciphering Developmental Disorders Study.

Nature. 2015 Mar 12;519(7542):223-8. doi: 10.1038/nature14135. Epub 2014 Dec 24.

PubMed [citation]

PMID:: 25533962
PMCID:: PMC5955210

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (6)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000222930.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000656484.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893796.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Pediatrics, MediClubGeorgia, SCV001468641.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	clinical testing (GTR000551760.4)	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided	(GTR000551760.4)	1	not provided	not provided	not provided

Last Updated: Aug 18, 2024

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