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

gnomAD frequency: 0.00003  dbSNP: rs576198476

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000332896	SCV000334157	uncertain significance	not provided	2015-08-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765701	SCV000897054	uncertain significance	Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV004529462	SCV000915927	uncertain significance	DCTN1-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	The DCTN1 c.414+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.00004 in the Total population from the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of splice donor variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for DCTN1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000765701	SCV001417110	uncertain significance	Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B	2023-05-25	criteria provided, single submitter	clinical testing	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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252080	SCV002523386	pathogenic	See cases	2019-04-05	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1, PM2, PP3
Ambry Genetics	RCV002328763	SCV002627215	likely benign	Inborn genetic diseases	2020-12-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.