Submissions for variant NM_022124.6(CDH23):c.3895G>A (p.Val1299Ile)

gnomAD frequency: 0.00027  dbSNP: rs201610096

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039166	SCV000062850	likely benign	not specified	2013-07-05	criteria provided, single submitter	clinical testing	Val1299Ile in Exon 32A of CDH23: This variant is not expected to have clinical s ignificance because it has been identified in 0.1% (1/593) of European chromosom es by the ClinSeq project and in 0.06% (5/8414) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs201610096), is reported as likely benign (Le Quesne Stabej 2012), and the val ine (Val) residue at position 1299 is not conserved in lower species with frog h aving an isoleucine (Ile).
Invitae	RCV001044674	SCV001208480	uncertain significance	not provided	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1299 of the CDH23 protein (p.Val1299Ile). This variant is present in population databases (rs201610096, gnomAD 0.03%). 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: 45932). 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 not expected to disrupt CDH23 protein function. 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.
Illumina Laboratory Services, Illumina	RCV001105662	SCV001262647	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). 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	RCV001105663	SCV001262648	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.
GeneDx	RCV001044674	SCV001873936	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Reported as likely benign in published literature due to lack of segregation with the phenotype but additional evidence is not available (Le Quesne et al., 2012; He et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22135276, 28900111)