NM_004408.4(DNM1):c.1335+1638G>A AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 23, 2022
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:: RCV000492949.5

Allele description [Variation Report for NM_004408.4(DNM1):c.1335+1638G>A]

NM_004408.4(DNM1):c.1335+1638G>A

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.1335+1638G>A

HGVS:

NC_000009.12:g.128226027G>A
NG_029726.1:g.27644G>A
NM_001005336.3:c.1335+1638G>A
NM_001288737.2:c.1197-8G>A
NM_001288738.2:c.1197-8G>A
NM_001288739.2:c.1197-8G>A
NM_004408.4:c.1335+1638G>AMANE SELECT
NC_000009.11:g.130988306G>A
NM_001288739.1:c.1197-8G>A
NM_004408.3:c.1335+1638G>A
c.1197-8G-A

Links:

OMIM: 602377.0006; dbSNP: rs747079285

NCBI 1000 Genomes Browser:

rs747079285

Molecular consequence:

NM_001005336.3:c.1335+1638G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001288737.2:c.1197-8G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001288738.2:c.1197-8G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001288739.2:c.1197-8G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_004408.4:c.1335+1638G>A - intron variant - [Sequence Ontology: SO:0001627]

Functional consequence:

probably has functional consequence

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000582119	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 26, 2022)	germline	clinical testing	Citation Link,
SCV003802785	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL CNVClassificationCriteria Aug2020)	Pathogenic (Aug 23, 2022)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32909139, 30097719, 36413998 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000582119

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 26, 2022)

germline

clinical testing

Citation Link,

SCV003802785

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL CNVClassificationCriteria Aug2020)

Pathogenic
(Aug 23, 2022)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Severe DNM1 encephalopathy with dysmyelination due to recurrent splice site pathogenic variant.

Sahly AN, Krochmalnek E, St-Onge J, Srour M, Myers KA.

Hum Genet. 2020 Dec;139(12):1575-1578. doi: 10.1007/s00439-020-02224-5. Epub 2020 Sep 9. No abstract available.

PubMed [citation]

PMID:: 32909139

Genome-wide investigation of an ID cohort reveals de novo 3'UTR variants affecting gene expression.

Devanna P, van de Vorst M, Pfundt R, Gilissen C, Vernes SC.

Hum Genet. 2018 Sep;137(9):717-721. doi: 10.1007/s00439-018-1925-9. Epub 2018 Aug 10.

PubMed [citation]

PMID:: 30097719
PMCID:: PMC6153495

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000582119.5

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

Description

Located in an alternative transcript of the gene; Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32909139, 30097719, 27535533)

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

From Illumina Laboratory Services, Illumina, SCV003802785.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The DNM1 c.1197-8G>A variant occurs in a splice region and results in the substitution of a guanine at nucleotide position c.1197-8 with an adenine. The variant is 8 bases upstream of exon 10a which is present in isoforms of DNM1 predominant in the brain, including the NM_001288739.1 transcript (PMID: 36413998). Three studies have reported the c.1197-8G>A variant in a presumed de novo state in ten individuals with developmental and epileptic encephalopathy (PMID: 30097719; PMID: 32909139;PMID: 36413998). This variant has been shown by minigene expression studies to result in the insertion of two amino acid residues (cystine and arginine) between arginine 399 and threonine 400. Structural analysis of the variant predicts that the insertion of two amino acid residues results in disruption of tetramerization, a process required to activate GTPase activity. This evidence suggests a dominant negative effect of the variant. Neuropathology analysis of brain tissue from an affected individual who was heterozygous for the variant showed abnormal vesicular fission and vesicle trafficking deficiency (PMID: 36413998). The c.1197-8G>A variant is not reported in the Genome Aggregation Database version 2.1.1 or 3.1.2. Based on the available evidence, the c.1197-8G>A variant is classified as pathogenic for developmental and epileptic encephalopathy.

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

Last Updated: Mar 30, 2024

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