ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 39 (MIM#6138093) and type 2A Usher syndrome (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 57 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated laminin EGF domain (Decipher). (I) 0801 - This variant has strong previous evidence of pathogenicity in multiple unrelated individuals with retinitis pigmentosa and Usher syndrome (ClinVar, PMID: 32893482). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 934 of the USH2A protein (p.Cys934Trp). This variant is present in population databases (rs201527662, gnomAD 0.2%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 25356976, 26338283, 27160483, 27460420, 29625443, 29899460, 30948794). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 143179). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

NM_206933.2(USH2A):c.2802T>G(C934W) is classified as likely pathogenic in the context of USH2A-related disorders. Sources cited for classification include the following: PMID 24938718, 25324289, 26310143, 27460420 and 26338283. Classification of NM_206933.2(USH2A):c.2802T>G(C934W) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000143179, PMID:21686329, PS1_S).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000202, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.849, PP3_P). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

Variant summary: USH2A c.2802T>G (p.Cys934Trp) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251078 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00021 vs 0.011), allowing no conclusion about variant significance. c.2802T>G has been reported in the literature as a biallelic genotype in multiple individuals affected with retinitis pigmentosa and Usher syndrome (e.g. Oishi_2014, Zheng_2015, Koyanagi_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fifteen ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, five classified the variant as likely pathogenic, and seven classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The USH2A, c.2802T>G (p.Cys934Trp) variant is at extremely low frequency in population database; allele frequency in East Asia population is 0. 0025 by gnomAD v2.1.1. This variant is detected in trans with a pathogenic variant [USH2A, c.9570+1G>A] . This variant has been previously reported to be detected in numerous patients affected by retinitis pigmentosa or Usher syndrome as homozygote [PMID: 26338283], or in combination with another null variant in USH2A gene [PMID: 24938718, 25649381, 30948794, 33105608, 26338283], including frameshift and canonical splice sites variants (c.8368delT, c.8730dupT, c.9570+1G>A, c.99_100insT, c.5858-1G>A, c.5158delC, c.11811_11812delCT, c.12409delA, c.710delT). In at least 3 patients, the other null variant was confirmed to be in trans with this variant [PMID: 24938718, 30948794]. Multiple lines of computational evidence support a deleterious effect on the gene or gene product, REVEL = 0.849. This variant has been reported to co-segregate with retinitis pigmentosa or Usher syndrome in several families [PMID: 24938718, 26310143, 21686329].There are multiple submissions of this variant in ClinVar (Variation ID: 143179).

The missense variant p.C934W in USH2A (NM_206933.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.C934W variant is observed in 46/18,376 (0.2503%) alleles from individuals of East Asian background in gnomAD Exomes and in 4/1,008 (0.3968%) alleles from individuals of East Asian background in 1000 Genomes. This variant was found in ClinVar (Variant 143179) with a classification of Conflicting Interpretations Of Pathogenicity and a review status of (1 star) criteria provided, conflicting interpretations. There is a large physicochemical difference between cysteine and tryptophan, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. For these reasons, this variant has been classified as Uncertain Significance. A different heterozygous variant in the USH2A gene has been detected in the spouse

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26992781, 29899460, 34416374, 33629268, 32531858, 31904091, 31045651, 31054281, 25262649, 25356976, 25474345, 26310143, 21686329, 24938718, 25324289, 27460420, 25649381, 25078356, 26338283, 28041643, 28704127, 29625443, 30487145, 29074561, 32100970, 31960602, 31213501, 32188678, 31872526, 30948794, 31456290, 32203226, 30896630, 32581362, 32893482, 33090715, 33105608, 34426522, 33124170, 32675063, 33608557, 31964843, 36464167, 36110214, 37981655, 33749171, 33781268, 33946315, 33691693, 32037395, 35314707, 34721897, 35266249, 35052368, 36597107, 36729443, 36819107)

Converted during submission to Pathogenic.