Submissions for variant NM_022124.6(CDH23):c.2236G>A (p.Val746Ile)

gnomAD frequency: 0.00021  dbSNP: rs550384315

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150283	SCV000197308	uncertain significance	not specified	2013-06-11	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Val746Ile varia nt in CDH23 has not been reported in individuals with hearing loss or in large p opulation studies. Computational analyses (biochemical amino acid properties, co nservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Of note, frog has a isoleucine (Ile) at this position despite high nearby amino acid conservation. In summary, the clinical s ignificance of this variant cannot be determined with certainty; however, based upon the arguments described above, we would lean towards a more likely benign r ole.
GeneDx	RCV000657974	SCV000779745	likely benign	not provided	2020-12-31	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18429043, 31054281, 32707200)
Fulgent Genetics, Fulgent Genetics	RCV000764912	SCV000896075	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000657974	SCV001029086	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001105264	SCV001262204	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	RCV001105265	SCV001262205	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.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001105265	SCV001572163	uncertain significance	Usher syndrome type 1D	2021-04-08	criteria provided, single submitter	research	The CDH23 c.2236G>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. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001105264	SCV002767256	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive deafness 12 (MIM#601386) and Usher syndrome type 1D (MIM#601067). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (30 heterozygotes, 2 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Cadherin domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Val746Leu) variant has been reported as unknown significance (Deafness Variation Database). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as uncertain significance, likely benign and benign in ClinVar. It has also been reported as likely pathogenic in an individual with retinal dystrophy who is also heterozygous for another missense variant in CDH23 and 2 variants in TTLL5 gene (PMID: 31054281, LOVD, Deafness Variation Database). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV000657974	SCV003831495	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001275937	SCV001461617	uncertain significance	Usher syndrome type 1	2020-04-15	no assertion criteria provided	clinical testing