11-17531408-C-CG
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_153676.4(USH1C):c.238dupC(p.Arg80ProfsTer69) variant causes a frameshift change. The variant allele was found at a frequency of 0.00031 in 1,613,748 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_153676.4 frameshift
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 rank | MANE | Protein | UniProt |
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USH1C | NM_153676.4 | c.238dupC | p.Arg80ProfsTer69 | frameshift_variant | Exon 3 of 27 | ENST00000005226.12 | NP_710142.1 | |
USH1C | NM_005709.4 | c.238dupC | p.Arg80ProfsTer69 | frameshift_variant | Exon 3 of 21 | ENST00000318024.9 | NP_005700.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH1C | ENST00000005226.12 | c.238dupC | p.Arg80ProfsTer69 | frameshift_variant | Exon 3 of 27 | 5 | NM_153676.4 | ENSP00000005226.7 | ||
USH1C | ENST00000318024.9 | c.238dupC | p.Arg80ProfsTer69 | frameshift_variant | Exon 3 of 21 | 1 | NM_005709.4 | ENSP00000317018.4 |
Frequencies
GnomAD3 genomes AF: 0.000197 AC: 30AN: 152190Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000280 AC: 70AN: 249768Hom.: 0 AF XY: 0.000244 AC XY: 33AN XY: 135060
GnomAD4 exome AF: 0.000322 AC: 471AN: 1461558Hom.: 0 Cov.: 31 AF XY: 0.000322 AC XY: 234AN XY: 727032
GnomAD4 genome AF: 0.000197 AC: 30AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74356
ClinVar
Submissions by phenotype
not provided Pathogenic:8
This sequence change creates a premature translational stop signal (p.Arg80Profs*69) in the USH1C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH1C are known to be pathogenic (PMID: 10973247, 17407589, 20301442, 21203349). This variant is present in population databases (rs397515359, gnomAD 0.2%). This premature translational stop signal has been observed in individuals with Usher syndrome type I (PMID: 10973248, 12702164, 17407589, 26969326). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5141). For these reasons, this variant has been classified as Pathogenic. -
PP1_moderate, PM2_supporting, PM3_very_strong, PVS1 -
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Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28041643, 31429209, 10973248, 11139240, 10973247, 22135276, 20301442, 30718709, 31980526, 32581362, 17407589, 12630964, 12702164, 27535533, 21569298, 12107438, 26969326) -
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Usher syndrome type 1C Pathogenic:6Other:1
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NM_153676.3(USH1C):c.238dupC(R80Pfs*69) is classified as pathogenic in the context of USH1C-related disorders. Sources cited for classification include the following: PMID 10973248 and 11139240. Classification of NM_153676.3(USH1C):c.238dupC(R80Pfs*69) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
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homozygous -
Recessive, congenital, profound HL;USH1C -
Usher syndrome Pathogenic:3
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Variant summary: USH1C c.238dupC (p.Arg80ProfsX69) 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 0.00028 in 249768 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH1C causing Usher Syndrome (0.00028 vs 0.0029), allowing no conclusion about variant significance. c.238dupC has been reported in the literature in the homozygous state in at least 1 individual affected with Usher Syndrome (example, Sloan-Heggen_2016). The following publication has been ascertained in the context of this evaluation (PMID: 26969326). ClinVar contains an entry for this variant (Variation ID: 5141). Based on the evidence outlined above, the variant was classified as pathogenic. -
Usher syndrome type 1 Pathogenic:2Other:1
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Autosomal recessive nonsyndromic hearing loss 18A Pathogenic:2
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Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Pathogenic:1
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USH1C-related disorder Pathogenic:1
The USH1C c.238dupC variant is predicted to result in a frameshift and premature protein termination (p.Arg80Profs*69). This variant has been reported to be causative for autosomal recessive Usher syndrome (Bitner-Glindzicz et al. 2000. PubMed ID: 10973248; Bujakowska et al. 2014. PubMed ID: 25468891; Ouyang et al. 2003. PubMed ID: 12630964; Table S3, Sloan-Heggen et al. 2016. PubMed ID: 26969326). This variant is reported in 0.20% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Frameshift variants in USH1C are expected to be pathogenic. This variant is interpreted as pathogenic. -
Hearing loss, autosomal recessive Pathogenic:1
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Rare genetic deafness Pathogenic:1
The p.Arg80fs variant in USH1C has been reported as a homozygous variant in at l east 5 individuals and as a compound heterozygous variant in at least 8 individu als with Usher syndrome, was absent in 552 control chromosomes, and segregated w ith a second pathogenic variant in 5 affected siblings (Bitner-Glindzicz 2000, B laydon 2003, Ebermann 2007, Le Quesne Stabej 2012, Ouyang 2003, Verpy 2000, Zwae nepoel 2001). It has been identified in 35/64768 European chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs148597 739); however, its frequency is low enough to be consistent with a recessive car rier frequency. This frameshift variant is predicted to alter the protein?s amin o acid sequence beginning at position 80 and lead to a premature termination cod on 69 amino acids downstream. This alteration is then predicted to lead to a tru ncated or absent protein. In summary, this variant meets our criteria to be clas sified as pathogenic for autosomal recessive Usher syndrome. -
Retinal dystrophy Pathogenic:1
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Retinitis pigmentosa Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at