11-17531408-C-CG

Variant names:

• chr11-17531408-C-CG
• rs397515359
• NM_153676.4:c.238dupC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:27 O:2
• Conservation: PhyloP100: 5.05

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]

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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
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: 30 AN: 152190 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000280 AC: 70 AN: 249768 AF XY: 0.000244

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 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

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33478

Gnomad4 AMR exome AF: 0.000313 AC: 14 AN: 44680

Gnomad4 ASJ exome AF: 0.00226 AC: 59 AN: 26130

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39694

Gnomad4 SAS exome AF: 0.000139 AC: 12 AN: 86204

Gnomad4 FIN exome AF: 0.0000187 AC: 1 AN: 53372

Gnomad4 NFE exome AF: 0.000329 AC: 366 AN: 1111860

Gnomad4 Remaining exome AF: 0.000298 AC: 18 AN: 60384

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74356

Gnomad4 AFR AF: 0.0000482 AC: 0.0000482486 AN: 0.0000482486

Gnomad4 AMR AF: 0.0000654 AC: 0.000065445 AN: 0.000065445

Gnomad4 ASJ AF: 0.00173 AC: 0.00172911 AN: 0.00172911

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000294 AC: 0.000293962 AN: 0.000293962

Gnomad4 OTH AF: 0.000478 AC: 0.000478469 AN: 0.000478469

Alfa AF: 0.000618 Hom.: 0

Bravo AF: 0.000174

EpiCase AF: 0.0000545

EpiControl AF: 0.000417

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 28, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 -

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

- -

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. -

May 27, 2022

Revvity Omics, Revvity

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

- -

Usher syndrome type 1C Pathogenic:6 Other:1

Jan 07, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

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. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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 -

Usher syndrome Pathogenic:3

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. -

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

- -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Usher syndrome type 1 Pathogenic:2 Other: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: flagged submission

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
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397515359; hg19: chr11-17552955; COSMIC: COSV50025881;