NM_004082.5(DCTN1):c.414+1G>A AND multiple conditions

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 25, 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:: RCV000765701.10

Allele description [Variation Report for NM_004082.5(DCTN1):c.414+1G>A]

NM_004082.5(DCTN1):c.414+1G>A

Gene:

DCTN1:dynactin subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p13.1

Genomic location:

Preferred name:

NM_004082.5(DCTN1):c.414+1G>A

HGVS:

NC_000002.12:g.74376741C>T
NG_008735.2:g.20347G>A
NM_001135040.3:c.393+691G>A
NM_001190836.2:c.342+691G>A
NM_001190837.2:c.393+691G>A
NM_001378991.1:c.363+1G>A
NM_001378992.1:c.363+1G>A
NM_004082.5:c.414+1G>AMANE SELECT
LRG_237t1:c.414+1G>A
LRG_237:g.20347G>A
NC_000002.11:g.74603868C>T
NM_004082.4:c.414+1G>A

Links:

dbSNP: rs576198476

NCBI 1000 Genomes Browser:

rs576198476

Molecular consequence:

NM_001135040.3:c.393+691G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001190836.2:c.342+691G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001190837.2:c.393+691G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001378991.1:c.363+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001378992.1:c.363+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_004082.5:c.414+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Amyotrophic lateral sclerosis type 1 (ALS1)
Synonyms:: AMYOTROPHIC LATERAL SCLEROSIS 1, FAMILIAL
Identifiers:: MONDO: MONDO:0007103; MedGen: C1862939; Orphanet: 803; OMIM: 105400

Name:: Perry syndrome
Synonyms:: Parkinsonism with alveolar hypoventilation and mental depression
Identifiers:: MONDO: MONDO:0008201; MedGen: C1868594; Orphanet: 178509; OMIM: 168605

Name:: Neuronopathy, distal hereditary motor, type 7B
Synonyms:: HMN VIIB; LOWER MOTOR NEURON DISEASE, DYNACTIN TYPE; NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 14; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011879; MedGen: C1843315; Orphanet: 139589; OMIM: 607641

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000897054	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001417110	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 25, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 33369814, 16199547, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000897054

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 31, 2018)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001417110

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 25, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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

Citations

PubMed

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; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Distal hereditary motor neuropathies: Mutation spectrum and genotype-phenotype correlation.

Frasquet M, Rojas-García R, Argente-Escrig H, Vázquez-Costa JF, Muelas N, Vílchez JJ, Sivera R, Millet E, Barreiro M, Díaz-Manera J, Turon-Sans J, Cortés-Vicente E, Querol L, Ramírez-Jiménez L, Martínez-Rubio D, Sánchez-Monteagudo A, Espinós C, Sevilla T, Lupo V.

Eur J Neurol. 2021 Apr;28(4):1334-1343. doi: 10.1111/ene.14700. Epub 2021 Jan 10. Erratum in: Eur J Neurol. 2022 Mar;29(3):955. doi: 10.1111/ene.15244.

PubMed [citation]

PMID:: 33369814

See all PubMed Citations (4)

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 Fulgent Genetics, Fulgent Genetics, SCV000897054.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001417110.6

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 282607). Disruption of this splice site has been observed in individual(s) with clinical features of distal hereditary motor neuropathy (PMID: 33369814). This variant is present in population databases (rs576198476, gnomAD 0.03%). This sequence change affects a donor splice site in intron 5 of the DCTN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in DCTN1 cause disease.

#	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

Last Updated: Nov 24, 2024

ClinVar

Relating variation to medicine