Submissions for variant NM_206933.4(USH2A):c.4189_4193dup (p.Ile1399fs)

dbSNP: rs1553313308

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670015	SCV000794823	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-10-17	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825553	SCV000966871	likely pathogenic	Rare genetic deafness	2018-05-10	criteria provided, single submitter	clinical testing	The p.Ile1399fs variant in USH2A has not been previously reported in individuals with hearing loss or Usher syndrome and was absent from large population studie s, though the ability of these studies to accurately detect indels may be limite d. This variant is predicted to cause a frameshift, which alters the protein?s a mino acid sequence beginning at position 1399 and leads to a premature terminati on codon 35 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the USH2A gene is an establi shed disease mechanism in autosomal recessive Usher syndrome. In summary, althou gh additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM2.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855533	SCV002157673	pathogenic	not provided	2023-08-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 554392). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile1399Metfs*35) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381).
Genome-Nilou Lab	RCV003453293	SCV004182261	likely pathogenic	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001829861	SCV004182263	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001829861	SCV002093904	likely pathogenic	Usher syndrome type 2A	2021-09-15	no assertion criteria provided	clinical testing