Submissions for variant NM_015404.4(WHRN):c.2234G>A (p.Arg745His)

gnomAD frequency: 0.00002  dbSNP: rs555619169

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001167912	SCV001330458	uncertain significance	Autosomal recessive nonsyndromic hearing loss 31	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001167913	SCV001330459	uncertain significance	Usher syndrome type 2D	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859087	SCV002223062	uncertain significance	not provided	2024-07-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 745 of the WHRN protein (p.Arg745His). This variant is present in population databases (rs555619169, gnomAD 0.09%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 25404053). ClinVar contains an entry for this variant (Variation ID: 913999). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV001167913	SCV003834937	uncertain significance	Usher syndrome type 2D	2021-05-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003490096	SCV004241155	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: WHRN c.2234G>A (p.Arg745His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 249952 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in WHRN causing Usher Syndrome (0.00017 vs 0.0038), allowing no conclusion about variant significance. c.2234G>A has been reported in the literature in an individual affected with Usher Syndrome, who also carried other potentially causitive variants (Aparisi_2014). This report does 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. The following publication have been ascertained in the context of this evaluation (PMID: 25404053). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.