rs786204428
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_174878.3(CLRN1):c.149_152delinsTGTCCAAT(p.Ser50LeufsTer12) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
CLRN1
NM_174878.3 frameshift
NM_174878.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.40
Genes affected
CLRN1 (HGNC:12605): (clarin 1) This gene encodes a protein that contains a cytosolic N-terminus, multiple helical transmembrane domains, and an endoplasmic reticulum membrane retention signal, TKGH, in the C-terminus. The encoded protein may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIIa. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-150972557-CCTG-ATTGGACA is Pathogenic according to our data. Variant chr3-150972557-CCTG-ATTGGACA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLRN1 | NM_174878.3 | c.149_152delinsTGTCCAAT | p.Ser50LeufsTer12 | frameshift_variant | 1/3 | ENST00000327047.6 | |
CLRN1 | NM_001195794.1 | c.149_152delinsTGTCCAAT | p.Ser50LeufsTer12 | frameshift_variant | 1/4 | ||
CLRN1 | NM_001256819.2 | c.149_152delinsTGTCCAAT | p.Ser50LeufsTer12 | frameshift_variant | 1/4 | ||
CLRN1 | NR_046380.3 | n.168_171delinsTGTCCAAT | non_coding_transcript_exon_variant | 1/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLRN1 | ENST00000327047.6 | c.149_152delinsTGTCCAAT | p.Ser50LeufsTer12 | frameshift_variant | 1/3 | 1 | NM_174878.3 | P1 | |
ENST00000469268.1 | n.236-29017_236-29014delinsATTGGACA | intron_variant, non_coding_transcript_variant | 4 | ||||||
CLRN1-AS1 | ENST00000476886.5 | n.124-90369_124-90366delinsATTGGACA | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Usher syndrome type 3 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 07, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Mar 17, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 19, 2017 | Variant summary: The CLRN1 c.149_152delinsTGTCCAAT (p.Ser50Leufs) variant results in a premature termination codon, predicted to cause a truncated or absent CLRN1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. This variant is absent in 122580 control chromosomes while it was reported in several patients with Usher Syndrome in homozygosity or in compound heterozygosity with other pathogenic variant indicating pathogenicity. In addition, multiple clinical diagnostic laboratories classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 24, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change creates a premature translational stop signal (p.Ser50Leufs*12) 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 (rs762606406, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 12145752, 22135276). This variant is also known as c.149delCAGGinsTGTCCAAT. ClinVar contains an entry for this variant (Variation ID: 1275768). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 13, 2016 | The c.149_152delCAGGinsTGTCCAAT pathogenic variant in the CLRN1 gene has been reportedpreviously in association with Usher syndrome type III (Fields et al., 2002; Le Quesne Stabej et al.,2012). The second study is a comprehensive clinical and genetic analysis of 172 Usher patientsincluding 2 families with Usher syndrome type III. In one of these families, segregation analysisconfirmed the c.149_152delCAGGinsTGTCCAAT pathogenic variant in a homozygous state (LeQuesne Stabej et al., 2012). The deletion and insertion causes a frameshift starting with codon Serine50, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 12 ofthe new reading frame, denoted p.Ser50LeufsX12. This pathogenic variant is predicted to cause lossof normal protein function either through protein truncation or nonsense-mediated mRNA decay. Thec.149_152delCAGGinsTGTCCAAT variant was not observed in approximately 6,500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations. Therefore, we consider this variant to be pathogenic. - |
Retinitis pigmentosa;C3280041:Retinitis pigmentosa 61;C5779850:Usher syndrome type 3A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 17, 2022 | - - |
Retinitis pigmentosa 61 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 30, 2023 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 30, 2017 | The p.Ser50fs variant in CLRN1 has been reported in 3 individuals with Usher syn drome type III, who were either homozygous for the variant or compound heterozyg ous for this variant and a second pathogenic variant (Fields 2002 and Le Quesne Stabej 2012). The variant has also been reported in ClinVar by multiple submitte rs as a pathogenic variant (Variation ID: 188726). It has also been identified i n 0.02% (27/126690) of European chromosomes by the Genome Aggregation Database ( gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs786204428); however this freq uency is low enough to be consistent with a recessive carrier frequency. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 50 and leads to a premature termination codon 12 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CLRN1 gene is an established disease mechanism in autosomal recessive Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome type III in an autos omal recessive manner. - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Feb 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at