rs727504301
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_033056.4(PCDH15):c.1927C>T(p.Arg643Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R643R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_033056.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCDH15 | NM_033056.4 | c.1927C>T | p.Arg643Ter | stop_gained | 16/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.1927C>T | p.Arg643Ter | stop_gained | 16/38 | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.1927C>T | p.Arg643Ter | stop_gained | 16/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.1927C>T | p.Arg643Ter | stop_gained | 16/38 | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000617 AC: 9AN: 1458212Hom.: 0 Cov.: 29 AF XY: 0.00000551 AC XY: 4AN XY: 725706
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Usher syndrome type 1F Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 07, 2018 | Variant summary: PCDH15 c.1927C>T (p.Arg643X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position have been classified as pathogenic by our laboratory (c.2971C>T (p.Arg991X)). The variant was absent in 246434 control chromosomes (gnomAD and publication data). c.1927C>T has been reported in the literature as a homozygous and compound heterozygous allele in multiple individuals affected with Usher Syndrome Type 1F (Ahmed 2003, Roux 2006). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 31, 2021 | - - |
Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 27, 2022 | - - |
Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 18, 2024 | - - |
Usher syndrome type 1D Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | Feb 01, 2019 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2023 | This sequence change creates a premature translational stop signal (p.Arg643*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 14570705). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177724). For these reasons, this variant has been classified as Pathogenic. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 10, 2014 | The Arg643X variant in PCDH15 has been reported in two individuals with Usher sy ndrome (Ahmed 2003, Roux 2006), and was not identified in large population studi es. Both of these individuals were homozygous or compound heterozygous with a se cond pathogenic variant and this variant segregated in two affected siblings. Th is nonsense variant leads to a premature termination codon at position 643, whic h is predicted to lead to a truncated or absent protein. In summary, this varian t meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/L MM). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at