Submissions for variant NM_206933.4(USH2A):c.11473del (p.His3825fs)

gnomAD frequency: 0.00001  dbSNP: rs774677256

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008825	SCV001168628	likely pathogenic	not provided	2019-01-03	criteria provided, single submitter	clinical testing	The c.11473delC variant in the USH2A gene has been reported previously in the homozygous state in affected individuals from a consanguineous Pakistani family with early onset retinal dystrophy (Maranhao et al., 2015). The c.11473delC variant causes a frameshift starting with codon Histidine 3825, changes this amino acid to an Isoleucine residue, and creates a premature Stop codon at position 10 of the new reading frame, denoted p.His3825IlefsX10. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.11473delC variant is observed in 4/30782 (0.013%) alleles from individuals of South Asian background in large population cohorts (Lek et al., 2016). We interpret c.11473delC as a likely pathogenic variant.
Invitae	RCV001008825	SCV002113756	pathogenic	not provided	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His3825Ilefs*10) 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). This variant is present in population databases (rs774677256, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with inherited retinal degeneration (PMID: 26352687). ClinVar contains an entry for this variant (Variation ID: 817630). For these reasons, this variant has been classified as Pathogenic.
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	RCV003389482	SCV003927125	pathogenic	Usher syndrome	2022-12-31	criteria provided, single submitter	research
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003338901	SCV004047575	likely pathogenic	Usher syndrome type 2A		criteria provided, single submitter	clinical testing	The frame shift (c.11473del) variant has been reported previously in homozygous state in patients affected with Usher syndrome, type 2A (Maranhao et al., 2015). The p.His3825IlefsTer10 variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0008% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. This variant causes a frameshift starting with codon Histidine 3825, changes this amino acid to Isoleucine residue, and creates a premature Stop codon at position 10 of the new reading frame, denoted p.His3825IlefsTer10. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed.
Genome-Nilou Lab	RCV003338901	SCV004182100	likely pathogenic	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467586	SCV004208383	pathogenic	Retinitis pigmentosa 39	2023-07-17	criteria provided, single submitter	clinical testing