Submissions for variant NM_004082.5(DCTN1):c.279G>C (p.Gln93His)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003321436	SCV004025854	likely pathogenic	not provided	2023-02-22	criteria provided, single submitter	clinical testing	Variant in the last nucleotide of the exon in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36608707, 19136952, 33210134, 34615428, 20945553, 33443672)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003777323	SCV004577839	likely pathogenic	Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change affects codon 93 of the DCTN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DCTN1 protein. This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with DCTN1-related conditions (PMID: 33443672; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2575870). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.