Submissions for variant NM_172364.5(CACNA2D4):c.548_554del (p.Leu183fs)

dbSNP: rs1210621191

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599103	SCV000710612	likely pathogenic	not provided	2018-02-02	criteria provided, single submitter	clinical testing	The c.548_554delTGGGCGC variant in the CACNA2D4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.548_554delTGGGCGC variant causes a frameshift starting with codon Leucine 183, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 16 of the new reading frame, denoted p.Leu183ProfsX16. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.548_554delTGGGCGC variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.548_554delTGGGCGC as a likely pathogenic variant.
Invitae	RCV000599103	SCV001484863	uncertain significance	not provided	2021-01-18	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. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CACNA2D4 cause disease. This variant has not been reported in the literature in individuals with CACNA2D4-related conditions. ClinVar contains an entry for this variant (Variation ID: 504297). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu183Profs*16) in the CACNA2D4 gene. It is expected to result in an absent or disrupted protein product.