Submissions for variant NM_022124.6(CDH23):c.4391C>T (p.Ala1464Val)

gnomAD frequency: 0.00020  dbSNP: rs374362883

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039181	SCV000062865	uncertain significance	not specified	2017-06-28	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ala1464Val va riant in CDH23 has been reported in 2 individuals with hearing loss; however in 1 of these individuals had an alternate etiology of the hearing loss identified (Shearer 2013, LMM unpublished data). This variant has also been identified in 0.03% (41/125814) of European chromosomes by the Genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org/; dbSNP rs374362883); however, its freque ncy is not high enough to rule out a pathogenic role. The alanine (Ala) at posi tion 1464 is not conserved in mammals or evolutionary distant species, with 1 ma mmal (gibbon) having a valine (Val), supporting that a change at this position c ould be tolerated. Additional computational prediction tools and conservation an alyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Ala1464Val variant is uncerta in, the conservation data suggests that it is more likely to be benign.
Fulgent Genetics, Fulgent Genetics	RCV000764918	SCV000896081	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
Illumina Laboratory Services, Illumina	RCV001106861	SCV001263970	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2018-01-12	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	RCV001106862	SCV001263971	uncertain significance	Usher syndrome type 1D	2018-01-12	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.
Invitae	RCV001244548	SCV001417776	uncertain significance	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1464 of the CDH23 protein (p.Ala1464Val). This variant is present in population databases (rs374362883, gnomAD 0.03%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 23804846). ClinVar contains an entry for this variant (Variation ID: 45947). 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 with a negative predictive value of 95%. 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.
GeneDx	RCV001244548	SCV001795892	likely benign	not provided	2020-07-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23804846)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039181	SCV002511871	uncertain significance	not specified	2022-04-08	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.4391C>T (p.Ala1464Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 246942 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (0.0002 vs 0.0032), allowing no conclusion about variant significance. c.4391C>T has been reported in the literature as a non-informative genotype (second allele and/or zygosity not specified) in settings of multigene panel testing in at-least one individual with deafness (example, Shearer_2014). These report(s) do 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5, Likely Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001273543	SCV001456680	uncertain significance	Usher syndrome type 1	2020-04-15	no assertion criteria provided	clinical testing