Submissions for variant NM_022124.6(CDH23):c.4520G>A (p.Arg1507Gln)

gnomAD frequency: 0.00007  dbSNP: rs373480195

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001107532	SCV001264685	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	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	RCV001107533	SCV001264686	uncertain significance	Usher syndrome type 1D	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	RCV001241875	SCV001414927	uncertain significance	not provided	2022-07-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1507 of the CDH23 protein (p.Arg1507Gln). This variant is present in population databases (rs373480195, gnomAD 0.03%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 15660226). ClinVar contains an entry for this variant (Variation ID: 879773). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001107533	SCV001573576	uncertain significance	Usher syndrome type 1D	2021-04-08	criteria provided, single submitter	research	The CDH23 c.4520G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PM3. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469345	SCV002766446	uncertain significance	not specified	2024-10-14	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.4520G>A (p.Arg1507Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 249110 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (6.8e-05 vs 0.0032), allowing no conclusion about variant significance. c.4520G>A has been reported in the literature in at least one homozygous individual affected with Usher Syndrome (Ouyang_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, however a minigene splicing assay demonstrated the variant has no impact on normal splicing (Becirovic_2008). The following publications have been ascertained in the context of this evaluation (PMID: 15660226, 18273900). ClinVar contains an entry for this variant (Variation ID: 879773). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002489753	SCV002787391	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2021-08-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001828558	SCV002087456	uncertain significance	Usher syndrome type 1	2020-02-11	no assertion criteria provided	clinical testing