Submissions for variant NM_022124.6(CDH23):c.8914G>A (p.Glu2972Lys)

gnomAD frequency: 0.00006  dbSNP: rs746716712

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519679	SCV000620782	uncertain significance	not provided	2018-09-14	criteria provided, single submitter	clinical testing	The E2972K variant in the CDH23 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E2972K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E2972K as a variant of uncertain significance.
Illumina Laboratory Services, Illumina	RCV001103062	SCV001259775	uncertain significance	Usher syndrome type 1D	2018-03-23	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	RCV001103063	SCV001259776	uncertain significance	Autosomal recessive nonsyndromic hearing loss 12	2018-03-23	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	RCV000519679	SCV003288456	uncertain significance	not provided	2022-03-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2972 of the CDH23 protein (p.Glu2972Lys). This variant is present in population databases (rs746716712, gnomAD 0.01%). 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: 452010). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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.
Ambry Genetics	RCV002525225	SCV003561551	uncertain significance	Inborn genetic diseases	2022-09-14	criteria provided, single submitter	clinical testing	The c.8914G>A (p.E2972K) alteration is located in exon 61 (coding exon 60) of the CDH23 gene. This alteration results from a G to A substitution at nucleotide position 8914, causing the glutamic acid (E) at amino acid position 2972 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001834705	SCV002092022	uncertain significance	Usher syndrome type 1	2019-10-28	no assertion criteria provided	clinical testing