Submissions for variant NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val)

gnomAD frequency: 0.00037  dbSNP: rs111033536

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001261015	SCV001438402	uncertain significance	Usher syndrome	2023-11-15	reviewed by expert panel	curation	The c.9569C>T variant (NM_022124.6(CDH23):c.9569C>T (p.Ala3190Val)) in CDH23 is a missense variant predicted to cause substitution of alanine by valine at amino acid 3190 (p.Ala3190Val). The highest minor allele frequency in gnomAD v4.0.0 is 694/1179698 alleles (0.0005517), in the European (non-Finnish) population (no population codes met). This variant has been observed in a homozygous state in one parent reported to have no features of Usher syndrome (BS2; Invitae internal data; ClinVar SCV001110059.2). The computational predictor REVEL gives a score of 0.836, which is above the Hearing Loss VCEP threshold of 0.7, evidence that correlates with impact to CDH23 function (PP3). The variant was found in a compound heterozygous state with a deletion of exon 29, a variant which was not able to be confirmed by aCGH (PMID: 25404053). The variant was also found in an unknown phase with p.Arg3206Cys (c.9616C>T), a variant of uncertain significance, in an affected patient with nonsyndromic hearing loss (PMID: 27068579; PM3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: BS2, PP3 (Version 2; 11/15/2023).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039313	SCV000062997	uncertain significance	not specified	2017-09-12	criteria provided, single submitter	clinical testing	The p.Ala3190Val variant in CDH23 has been reported in 1 individual with Usher s yndrome who also had a duplication of exon 29 in CDH23 that is of uncertain sign ificance (Aparisi 2014), and in 1 individual with hearing loss who also had the p.Arg3206Cys variant of uncertain significance in CDH23 (Sommen 2016). The p.Ala 3190Val variant has also been identified by our laboratory in the heterozygous s tate in 3 individuals with hearing loss; however, a variant affecting the remain ing copy of CDH23 was not identified in any of these individuals. This variant h as been identified in 0.08% (8/10122) of Ashkenazi Jewish chromosomes and 0.05% (64/126200) European chromosomes by Genome Aggregation Database (gnomAD, http:// gnomad.broadinstitute.org; dbSNP rs111033536). Although this variant has been se en in the general population, its frequency is not high enough to rule out a pat hogenic role. Computational prediction tools and conservation analyses suggest t hat this variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, the clinical significance of t he p.Ala3190Val variant is uncertain.
GeneDx	RCV000766715	SCV000564847	uncertain significance	not provided	2022-06-17	criteria provided, single submitter	clinical testing	Identified in a patient with nonsyndromic hearing loss, along with a second variant with unknown phase in published literature (Sommen et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25404053, 27068579, 30245029, 32387678)
Fulgent Genetics, Fulgent Genetics	RCV000763669	SCV000894549	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12; Usher syndrome type 1D; Pituitary adenoma 5, multiple types	2022-05-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV004528198	SCV000915480	uncertain significance	CDH23-related disorder	2017-12-05	criteria provided, single submitter	clinical testing	The CDH23 c.9569C>T (p.Ala3190Val) missense variant has been reported in two studies in which it is identified in a compound heterozygous state in two individuals, one with a diagnosis of Usher syndrome and one with autosomal recessive nonsyndromic hearing loss (Aparisi et al. 2014; Sommen et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. Based on the evidence, the p.Ala3190Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for CDH23-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000766715	SCV001110059	benign	not provided	2024-01-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766715	SCV001246549	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing	CDH23: PP3
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375340	SCV001572058	likely pathogenic	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PS1_Moderate, PM2_Moderate, PP3_Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039313	SCV002500713	uncertain significance	not specified	2023-09-13	criteria provided, single submitter	clinical testing	Variant summary: CDH23 c.9569C>T (p.Ala3190Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 247998 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CDH23 causing Usher Syndrome (0.00034 vs 0.0032), allowing no conclusion about variant significance. c.9569C>T has been reported in the literature in individuals with hearing loss (e.g., Aparisi_2014, Sommen_2016, Clabout_2022), however without strong evidence of causality in all cases (e.g., lack of a second confirmed CDH23 allele and/or segregation/phase not determined). This variant was also listed as an expert curated classification of "likely pathogenic" in the Deafness Variation Database (DVD) (e.g., Azaiez_2018) and cited by others (e.g., Chen_2019). These reports therefore 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. The following publications have been ascertained in the context of this evaluation (PMID: 25404053, 30245029, 27068579, 36672845, 31445392). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=6; Likely pathogenic, n=1; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003473286	SCV004210580	uncertain significance	Pituitary adenoma 5, multiple types	2023-10-30	criteria provided, single submitter	clinical testing