Variant: NM_206933.3(USH2A):c.5516T>A (p.Val1839Glu)

CA10588918

265979 (ClinVar)

Gene: USH2A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

UUID: 949b8408-a95d-4d9c-836f-b9f8ae51effb

HGVS expressions

NM_206933.3:c.5516T>A
NM_206933.3(USH2A):c.5516T>A (p.Val1839Glu)
NC_000001.11:g.216078145A>T
CM000663.2:g.216078145A>T
NC_000001.10:g.216251487A>T
CM000663.1:g.216251487A>T
NC_000001.9:g.214318110A>T
NG_009497.1:g.350252T>A
NG_009497.2:g.350304T>A
ENST00000307340.8:c.5516T>A
ENST00000674083.1:c.5516T>A
ENST00000307340.7:c.5516T>A
NM_206933.2:c.5516T>A
NR_125992.1:n.137-928A>T
NR_125993.1:n.136+5545A>T
NM_206933.4:c.5516T>A
NM_206933.4(USH2A):c.5516T>A (p.Val1839Glu)

Likely Pathogenic

• Met criteria codes: PP4 PM2_Supporting PM3_Strong

• Not Met criteria codes: PP3

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The c.5516T>A variant in USH2A is a missense variant predicted to cause substitution of valine to glutamate at amino acid position 1839. The variant was absent from gnomAD v2.1.1 and present in 0.001549% (1/64578) of non-Finnish European chromosomes in gnomAD v3 (PM2_Supporting). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been detected in at least 4 individuals (2 with Usher syndrome and 2 with isolated retinitis pigmentosa) (total of 2.5 PM3 points, PM3_Strong). One individual with Usher syndrome was assumed to be compound heterozygous with a pathogenic c.2299del variant, but phase unknown (VCV000002351.78; PMID: 26927203). The other two individuals had retinitis pigmentosa and were assumed compound heterozygous with pathogenic p.(Cys759Phe) variant (VCV000002356.89; PMID: 26927203; PMID: 34203967). One patient displayed both retinal degradation and sensorineural hearing loss, features highly specific for USH2A (PP4). Patients with this variant may present with either Usher syndrome or with isolated RP. Isolated RP presentations are more common when the variant is seen with missense variants while Usher syndrome is more common when it is found with truncating variants. In summary, the clinical significance of this variant is likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: PM2_Supporting, PM3_Strong, PP4 (VCEP specifications version 2; 10.18.2023).

Met criteria codes

• PP4: 1 patient proband had a diagnosis of retinal degeration and sensorineural hearing loss.
• PM2_Supporting: Absent from gnomAD v2. Present in 0.001470% (1/68036) of non-Finnish European chromosomes in gnomAD v3.
• PM3_Strong: 2.5 PM3 points from 4 individuals (2 with Usher Syndrome and 2 with reinitis pigmentosa) who were assumed compound heterozygous with pathogenics variant. Reports from Neuhaus et al; Pierrache et al; Janine Reurink et al.

Not Met criteria codes

• PP3: REVEL score 0.556. Not present in any animals in UCSC database. Splicing is not predicted to be impacted using Alamut.

Approved on: 2023-10-18

Published on: 2024-01-10