rs754391973
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_033056.4(PCDH15):c.2971C>T(p.Arg991Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,610,698 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 (★★). 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.2971C>T | p.Arg991Ter | stop_gained | 22/33 | ENST00000320301.11 | |
PCDH15 | NM_001384140.1 | c.2971C>T | p.Arg991Ter | stop_gained | 22/38 | ENST00000644397.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCDH15 | ENST00000320301.11 | c.2971C>T | p.Arg991Ter | stop_gained | 22/33 | 1 | NM_033056.4 | ||
PCDH15 | ENST00000644397.2 | c.2971C>T | p.Arg991Ter | stop_gained | 22/38 | NM_001384140.1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152040Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 250854Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135594
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1458658Hom.: 0 Cov.: 30 AF XY: 0.00000965 AC XY: 7AN XY: 725606
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152040Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74264
ClinVar
Submissions by phenotype
Usher syndrome type 1F Pathogenic:2
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | The p.Arg991Ter variant in PCDH15 has been reported in at least 2 individuals with Usher syndrome type 1F (PMID: 16679490, 32531858), and has been identified in 0.004% (4/113468) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs754391973). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 224747) and has been interpreted as pathogenic by Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Invitae, and Centre for Genomic Medicine (Central Manchester University Hospitals). Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Arg991Ter variant is pathogenic (PMID: 32531858). This nonsense variant leads to a premature termination codon at position 991, which is predicted to lead to a truncated or absent protein. Loss of function of the PCDH15 gene is an established disease mechanism in autosomal recessive Usher syndrome type 1F. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3 (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 02, 2018 | Variant summary: PCDH15 c.2971C>T (p.Arg991X) 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. The variant allele was found at a frequency of 2e-05 in 246060 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (2e-05 vs 0.0032), allowing no conclusion about variant significance. The c.2971C>T variant has been reported in the literature in multiple homozygous individuals affected with Usher Syndrome Type 1F. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 05, 2024 | - - |
Usher syndrome type 1D Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | Aug 28, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | This premature translational stop signal has been observed in individual(s) with clinical features of Usher syndrome (PMID: 16679490, 24618850, 29568747). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Arg991*) 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 present in population databases (rs754391973, gnomAD 0.004%). This variant is also known as c.2758C>T (p.R920*). ClinVar contains an entry for this variant (Variation ID: 224747). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at