Submissions for variant NM_032119.4(ADGRV1):c.17668_17669del (p.Met5890fs) (rs757696771)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599234	SCV000709808	pathogenic	not provided	2018-03-05	criteria provided, single submitter	clinical testing	The c.17668_17669delAT variant has been published previously in association with Usher syndrome (Bonnet et al., 2011). The variant is observed in 2/15244 (0.013%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The variant causes a frameshift starting with codon Methionine 5890, changes this amino acid to a Valine residue and creates a premature Stop codon at position 10 of the new reading frame, denoted p.Met5890ValfsX10. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we consider this variant to be pathogenic.
Mendelics	RCV000987544	SCV001136860	pathogenic	Usher syndrome, type 2C	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV000599234	SCV001380629	pathogenic	not provided	2019-10-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met5890Valfs*10) in the ADGRV1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs757696771, ExAC 0.01%). This variant has been observed in an individual affected with Usher syndrome (PMID: 21569298). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in ADGRV1 are known to be pathogenic (PMID: 19357117, 22135276, 22147658). For these reasons, this variant has been classified as Pathogenic.