Submissions for variant NM_022124.6(CDH23):c.3092G>C (p.Ser1031Thr)

gnomAD frequency: 0.00001  dbSNP: rs397517320

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039142	SCV000062826	uncertain significance	not specified	2014-08-11	criteria provided, single submitter	clinical testing	The Ser1031Thr variant in CDH23 has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational pr ediction tools and conservation analysis suggest that this variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the Ser1031Thr variant is uncer tain.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757073	SCV000885165	uncertain significance	not provided	2018-01-23	criteria provided, single submitter	clinical testing	The p.Ser1031Thr variant (rs397517320) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) identified on a single chromosome out of 30,944, and has been reported to the ClinVar database as a variant of uncertain significance (Variation ID: 45909). The serine at position 1031 is highly conserved up to zebrafish considering 12 species (Alamut v2.10) and computational analyses of the effects of the p.Ser1031Thr variant on protein structure and function provide conflicting results (SIFT:tolerated, MutationTaster: disease causing, PolyPhen-2:possibly damaging). Altogether, there is not enough evidence to classify the p.Ser1031Thr variant with certainty.
Illumina Laboratory Services, Illumina	RCV001106595	SCV001263671	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	RCV001106596	SCV001263672	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000757073	SCV002307598	uncertain significance	not provided	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1031 of the CDH23 protein (p.Ser1031Thr). This variant is present in population databases (rs397517320, 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: 45909). 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.
Ambry Genetics	RCV002513525	SCV003664071	uncertain significance	Inborn genetic diseases	2022-11-08	criteria provided, single submitter	clinical testing	The c.3092G>C (p.S1031T) alteration is located in exon 26 (coding exon 25) of the CDH23 gene. This alteration results from a G to C substitution at nucleotide position 3092, causing the serine (S) at amino acid position 1031 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001271860	SCV001453332	uncertain significance	Usher syndrome type 1	2020-09-16	no assertion criteria provided	clinical testing