3-150972520-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_174878.3(CLRN1):c.189C>A(p.Tyr63*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,058 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_174878.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251460Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135896
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727246
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74332
ClinVar
Submissions by phenotype
Usher syndrome type 3 Pathogenic:4
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Variant summary: CLRN1 c.189C>A (p.Tyr63X) 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 1.8e-05 in 277198 control chromosomes. c.189C>A has been reported in the literature as a homozygous and compound heterozygous allele in multiple individuals affected with Usher Syndrome Type 3 (Adato_2002; Garcia-Garcia_2012). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Usher syndrome type 3A Pathogenic:2
The CLRN1 c.189C>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1. Based on this evidence we have classified this variant as Pathogenic. -
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004397, PMID:12080385). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000014, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
CLRN1-related disorder Pathogenic:1
The CLRN1 c.189C>A variant is predicted to result in premature protein termination (p.Tyr63*). This variant has been reported to be causative for autosomal recessive Usher syndrome or retinitis pigmentosa (Adato et al. 2002. PubMed ID: 12080385; Melo et al. 2014. PubMed ID: 24596593; Carss et al. 2016. PubMed ID: 28041643). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-150690307-G-T). Nonsense variants in CLRN1 are expected to be pathogenic. Given the evidence, we interpret c.189C>A (p.Tyr63*) as pathogenic. -
Retinitis pigmentosa 61;C5779850:Usher syndrome type 3A Pathogenic:1
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Retinitis pigmentosa 61 Pathogenic:1
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not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Tyr63*) in the CLRN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLRN1 are known to be pathogenic (PMID: 11524702, 24498627). This variant is present in population databases (rs111033267, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 12080385, 23304067). ClinVar contains an entry for this variant (Variation ID: 4397). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Rare genetic deafness Pathogenic:1
The Tyr63X variant in CLRN1 has been reported in a homozygous state in three sib lings with Usher syndrome from one family (Adato 2002, Aller 2004). This nonsens e variant leads to a premature termination codon at position 63, which is predic ted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -
Retinitis pigmentosa Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at