Submissions for variant NM_183357.3(ADCY5):c.2026dup (p.Ala676fs)

dbSNP: rs151195921

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480522	SCV000572887	uncertain significance	not specified	2017-01-25	criteria provided, single submitter	clinical testing	The c.2026dupG variant in the ADCY5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Alanine 676, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Ala676GlyfsX2. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2026dupG variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2026dupG as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856871	SCV002166490	pathogenic	not provided	2021-12-13	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 423222). This sequence change creates a premature translational stop signal (p.Ala676Glyfs*2) in the ADCY5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADCY5 are known to be pathogenic (PMID: 28971144, 34631954). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dystonia (Invitae). For these reasons, this variant has been classified as Pathogenic.