11-17531408-CG-CGG

Position:

chr11-17531408-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000318024.9(USH1C):c.238_239insC(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
ENST00000318024.9 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]

USH1C links:

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/exons	MANE	Protein	UniProt
USH1C	NM_005709.4 linkuse as main transcript	c.238_239insC	p.Arg80ProfsTer69	frameshift_variant	3/21	ENST00000318024.9	NP_005700.2
USH1C	NM_153676.4 linkuse as main transcript	c.238_239insC	p.Arg80ProfsTer69	frameshift_variant	3/27	ENST00000005226.12	NP_710142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 linkuse as main transcript	c.238_239insC	p.Arg80ProfsTer69	frameshift_variant	3/27	5	NM_153676.4	ENSP00000005226		Q9Y6N9-5
USH1C	ENST00000318024.9 linkuse as main transcript	c.238_239insC	p.Arg80ProfsTer69	frameshift_variant	3/21	1	NM_005709.4	ENSP00000317018	P1	Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152190

Hom.:

Cov.:

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:

AN:

249768

Hom.:

AF XY:

0.000244

AC XY:

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.:

Cov.:

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:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

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.:

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

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 03, 2021	PP1_moderate, PM2_supporting, PM3_very_strong, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 27, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 28, 2017	- -

Usher syndrome type 1C

Pathogenic:6Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	NM_153676.3(USH1C):c.238dupC(R80Pfs69) 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(R80Pfs69) 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	May 07, 2018	Recessive, congenital, profound HL;USH1C -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 29, 2024	homozygous -

Usher syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	research	SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	Dec 31, 2022	- -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 09, 2024	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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Autosomal recessive nonsyndromic hearing loss 18A

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 03, 2017	- -

Usher syndrome type 1;C1848604:Usher syndrome type 1C;C1865870:Autosomal recessive nonsyndromic hearing loss 18A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 09, 2022

- -

USH1C-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2024

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

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 26, 2015

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

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Feb 27, 2019

- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over