Submissions for variant NM_022124.6(CDH23):c.429+4G>A

gnomAD frequency: 0.00003  dbSNP: rs397517328

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001089681	SCV001245165	benign	Nonsyndromic genetic hearing loss	2020-01-15	reviewed by expert panel	curation	The filtering allele frequency of the c.429+4G>A variant in CDH23 is 1.13% for South Asian chromosomes by gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). This silent variant in CDH23 is not predicted by the computational prediction analysis using MaxEntScan to impact splicing (BP7, BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel (BA1, BP7, BP4).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039175	SCV000062859	uncertain significance	not specified	2014-08-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The 429+4G>A varian t in CDH23 has been previously reported in two Asian families with hearing loss; however, both probands were heterozygous and a variant affecting the remaining CDH23 allele was not identified (LMM unpublished data; Ganapathy 2014). This var iant has not been identified in large population studies, but there is an insuff icient number of Asian chromosomes in these studies to assess the frequency of t he variant in the Asian population. This variant is located in the 5' splice reg ion. Computational tools do not suggest an impact to splicing and this nucleotid e position is not conserved, yet, this information is not predictive enough to r ule out pathogenicity. In summary, while the clinical significance of the 429+4G >A variant is uncertain, these data suggest that is more likely to be benign.
GeneDx	RCV000941279	SCV000521014	benign	not provided	2019-02-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30245029, 24416283, 29148562, 30718709)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000941279	SCV001087162	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001103055	SCV001259768	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2017-04-27	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.
Illumina Laboratory Services, Illumina	RCV001103056	SCV001259769	uncertain significance	Usher syndrome type 1D	2017-04-27	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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787808	SCV000926818	likely pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research