ClinVar

Description

Variant summary: USH2A c.4027A>C (p.Asn1343His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251046 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0001 vs 0.011), allowing no conclusion about variant significance. c.4027A>C has been reported in the literature in heterozygosity along with another phase unspecified USH2A variant (c.7358T>A, p.Val2453Asp) in one individual with Retinitis Pigmentosa who underwent whole genome sequencing (WGS) (example, Carss_2017, subsequently cited by Molina-Ramirez_2020). It was also reported in heterozygosity along with another heterozygous phase unspecified USH2A variant (c.2108A>T, p.D703V) in an individual with sporadic Retinitis Pigmentosa who harbored a homozygous variant in the TULP1 gene (c.629C>G, p.S210X) that was stated as likely causative of disease (example, Glockle_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely pathogenic, n=1; VUS, n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.