chr10-71734271-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_022124.6(CDH23):c.4136G>T(p.Arg1379Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1379C) has been classified as Uncertain significance.
Frequency
Consequence
NM_022124.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDH23 | NM_022124.6 | c.4136G>T | p.Arg1379Leu | missense_variant | 33/70 | ENST00000224721.12 | |
C10orf105 | NM_001168390.2 | c.-6+3457C>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDH23 | ENST00000224721.12 | c.4136G>T | p.Arg1379Leu | missense_variant | 33/70 | 5 | NM_022124.6 | P1 | |
C10orf105 | ENST00000398786.2 | c.-6+3457C>A | intron_variant | 2 | P1 | ||||
CDH23 | ENST00000398792.3 | n.828G>T | non_coding_transcript_exon_variant | 5/9 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Pituitary adenoma 5, multiple types Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 26, 2017 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 22, 2023 | Variant summary: CDH23 c.4136G>T (p.Arg1379Leu) results in a non-conservative amino acid change located in a calcium binding site of extracellular cadherin 13 domain (Zhang_2017) of the encoded protein sequence. This alters a highly conserved residue in which another missense variant (p.R1379P) has been found in association with Usher syndrome (HGMD). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245062 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4136G>T has been reported in the literature in related heterozygous individuals affected with pituitary adenoma without a second variant identified and without retinal phenotyping (Zhang_2017). This reports does 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 publication has been ascertained in the context of this evaluation (PMID: 28413019). One submitter (OMIM) has cited a clinical-significance assessment for this variant to ClinVar after 2014 under the condition of pituitary adenoma, and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at