ClinVar Miner

Submissions for variant NM_004393.6(DAG1):c.454_467del (p.Phe152fs) (rs1553652513)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000533805 SCV000650625 likely pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C9; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 9 2018-09-05 criteria provided, single submitter clinical testing This sequence change deletes 14 nucleotides from exon 3 of the DAG1 mRNA (c.454_467delTTCTCCATCGAGGT), causing a frameshift at codon 152. This creates a premature translational stop signal in the last exon of the DAG1 mRNA (p.Phe152Leufs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt amino acids 152-154 and delete the last 742 amino acids of the DAG1 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DAG1-related disease. A different truncating variant (p.Ala248Glufs*19) downstream of this variant has been determined to be pathogenic (PMID: 25934851). This suggests that the C-terminal residues deleted as a result of this variant are critical for DAG1 protein function and that upstream truncations may also be pathogenic. In summary, this variant is a novel truncation that deletes a significant portion of the DAG1 protein and occurs upstream of a previously reported pathogenic truncation. This evidence indicates that this variant is pathogenic, but additional data is needed to conclusively establish its role in disease. Therefore, this variant has been classified as Likely Pathogenic.

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