Submissions for variant NM_022124.6(CDH23):c.2059+6G>A

gnomAD frequency: 0.00008  dbSNP: rs727502923

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150280	SCV000197305	uncertain significance	not specified	2013-05-31	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The 2059+6G>A varia nt in CDH23 has been reported in 1/244 of chromosomes without additional informa tion (Deafness Variant Database; http://deafnessvariationdatabase.org). This var iant is located in the 5' splice region, but not in the invariant +1/+2 splice s ite positions. Computational tools do not suggest an impact to splicing and this nucleotide position is not conserved across species; though, this information i s not predictive enough to rule out pathogenicity. In summary, the clinical sign ificance of this variant cannot be determined; however, based on the lack of con servation at this position as well as the computational data, we would lean towa rds a likely benign role.
Illumina Laboratory Services, Illumina	RCV001103350	SCV001260096	uncertain significance	Usher syndrome type 1D	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001103351	SCV001260097	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514889	SCV003283658	uncertain significance	not provided	2022-05-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 19 of the CDH23 gene. It does not directly change the encoded amino acid sequence of the CDH23 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs727502923, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with CDH23-related conditions. ClinVar contains an entry for this variant (Variation ID: 162890). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Natera, Inc.	RCV001826803	SCV002085483	uncertain significance	Usher syndrome type 1	2019-10-28	no assertion criteria provided	clinical testing