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

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

USH1C
NM_153676.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:27O:2

Conservation

PhyloP100: 5.05
Variant links:
Genes affected
USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

Genome browser will be placed here

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 11-17531408-C-CG is Pathogenic according to our data. Variant chr11-17531408-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 5141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USH1CNM_153676.4 linkc.238dupC p.Arg80ProfsTer69 frameshift_variant Exon 3 of 27 ENST00000005226.12 NP_710142.1 Q9Y6N9-5
USH1CNM_005709.4 linkc.238dupC p.Arg80ProfsTer69 frameshift_variant Exon 3 of 21 ENST00000318024.9 NP_005700.2 Q9Y6N9-1A0A0S2Z4U9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USH1CENST00000005226.12 linkc.238dupC p.Arg80ProfsTer69 frameshift_variant Exon 3 of 27 5 NM_153676.4 ENSP00000005226.7 Q9Y6N9-5
USH1CENST00000318024.9 linkc.238dupC p.Arg80ProfsTer69 frameshift_variant Exon 3 of 21 1 NM_005709.4 ENSP00000317018.4 Q9Y6N9-1

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152190
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000294
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000280
AC:
70
AN:
249768
Hom.:
0
AF XY:
0.000244
AC XY:
33
AN XY:
135060
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000378
Gnomad ASJ exome
AF:
0.00199
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000310
Gnomad OTH exome
AF:
0.000328
GnomAD4 exome
AF:
0.000322
AC:
471
AN:
1461558
Hom.:
0
Cov.:
31
AF XY:
0.000322
AC XY:
234
AN XY:
727032
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.00226
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000139
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000329
Gnomad4 OTH exome
AF:
0.000298
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152190
Hom.:
0
Cov.:
33
AF XY:
0.000175
AC XY:
13
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000294
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000618
Hom.:
0
Bravo
AF:
0.000174
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000417

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:27Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:8
Dec 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Aug 03, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP1_moderate, PM2_supporting, PM3_very_strong, PVS1 -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 28, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Jul 13, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 28, 2017
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 27, 2022
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Usher syndrome type 1C Pathogenic:6Other:1
Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 17, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jan 07, 2021
Genetics and Molecular Pathology, SA Pathology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 01, 2001
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Aug 29, 2024
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

homozygous -

May 07, 2018
Laboratory of Prof. Karen Avraham, Tel Aviv University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Recessive, congenital, profound HL;USH1C -

Usher syndrome Pathogenic:3
Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Dec 31, 2022
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Sep 09, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jun 23, 2019
Sharon lab, Hadassah-Hebrew University Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

-
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Autosomal recessive nonsyndromic hearing loss 18A Pathogenic:2
Mar 30, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 03, 2017
Counsyl
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A Pathogenic:1
Feb 29, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

USH1C-related disorder Pathogenic:1
Sep 23, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
-
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Rare genetic deafness Pathogenic:1
Jul 26, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Feb 27, 2019
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinitis pigmentosa Pathogenic:1
Apr 01, 2018
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397515359; hg19: chr11-17552955; API