Submissions for variant NM_004082.5(DCTN1):c.279+1G>T

dbSNP: rs1393363759

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685402	SCV000812880	pathogenic	Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B	2023-03-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 565763). Disruption of this splice site has been observed in individual(s) with clinical features of hereditary motor neuropathy (PMID: 25590979; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects a donor splice site in intron 2 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.
Athena Diagnostics	RCV000991877	SCV001143712	pathogenic	not provided	2024-06-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with Perry syndrome. This variant is expected to impact normal RNA splicing. Though the reading frame of the transcript is expected to be maintained, an important region of the protein is disrupted, therefore, this variant is expected to severely disrupt function. A variant expected to cause the same impact in normal RNA splicing has been confirmed to occur de novo in multiple individuals with Perry syndrome.
GeneDx	RCV000991877	SCV001773753	likely pathogenic	not provided	2019-05-10	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of a critical region (CAP-Gly domain and GKNDG motif); A different nucleotide change at this same splice donor site (c.279+2T>C) has been reported in an individual with muscle wasting, weakness, and fasciculations (Zhu et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously reported as pathogenic or benign to our knowledge
Inherited Neuropathy Consortium	RCV001027493	SCV001190068	likely pathogenic	Hereditary motor neuron disease		no assertion criteria provided	provider interpretation