rs151045328

Positions:

chr11-17531431-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_153676.4(USH1C):c.216G>A(p.Val72Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

USH1C
NM_153676.4 synonymous

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16O:2

Conservation

PhyloP100: 3.44

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:

USH1C (HGNC:):

USH1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-17531431-C-T is Pathogenic according to our data. Variant chr11-17531431-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17531431-C-T is described in Lovd as [Pathogenic]. Variant chr11-17531431-C-T is described in Lovd as [Pathogenic]. Variant chr11-17531431-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4 linkuse as main transcript	c.216G>A	p.Val72Val	synonymous_variant	3/27	ENST00000005226.12	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4 linkuse as main transcript	c.216G>A	p.Val72Val	synonymous_variant	3/21	ENST00000318024.9	NP_005700.2	Q9Y6N9-1A0A0S2Z4U9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 linkuse as main transcript	c.216G>A	p.Val72Val	synonymous_variant	3/27	5	NM_153676.4	ENSP00000005226.7		Q9Y6N9-5
USH1C	ENST00000318024.9 linkuse as main transcript	c.216G>A	p.Val72Val	synonymous_variant	3/21	1	NM_005709.4	ENSP00000317018.4		Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251060

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000227

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change affects codon 72 of the USH1C mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the USH1C protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs151045328, gnomAD 0.008%). This variant has been observed in individuals with Usher syndrome 1C (PMID: 11810303, 15578223, 15660226, 17407589). It is commonly reported in individuals of Acadian ancestry (PMID: 17407589, 18665195). ClinVar contains an entry for this variant (Variation ID: 5143). Studies have shown that this variant results in introduction of a cryptic splice site and introduces a premature termination codon (PMID: 10973248, 15578223). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
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	GeneDx	Dec 22, 2021	cDNA analysis demonstrated that the c.216 G>A variant creates a new splice site and results in an out-of-frame deletion of 35 nucleotides (Bitner Glindzicz et al., 2000; Lentz et al., 2005); This variant is associated with the following publications: (PMID: 23380860, 12630964, 17407589, 11139240, 21228398, 28041643, 10973248, 15578223, 21436283, 11810303, 29276601, 32581362, 33089500) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 24, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Usher syndrome type 1C

Pathogenic:3Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 10, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 26, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0209 - Splice variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with uncertain effect on protein structure (exon 3 of 27) (PMID: PMID: 10973248, 15578223, 20613545). (P) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (P) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant is known as the Acadian allele which causes the most severe form of Usher syndrome type 1 (ClinVar, Deafness Variation Database, PMID: 29276601). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2002	- -

Autosomal recessive nonsyndromic hearing loss 18A

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 14, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2024	- -

Usher syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2022	Variant summary: USH1C c.216G>A alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic exonic 5' splice donor site located two base bairs proximal to this variant. At least one publication reports experimental evidence that this variant affects mRNA splicing due to the creation of a new splice site within exon 3 two base pairs proximal to the site of this variant (Bitner-Glindzicz_2000). The variant allele was found at a frequency of 3.6e-05 in 251060 control chromosomes. c.216G>A has been reported in the literature as a founder mutation of Acadian origin in homozygous and compound heterozygous genotypes among individuals affected with Usher Syndrome (example, Quyang_2003, Bukakowska_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence from a knock in mouse model that demonstrated early onset dual impairment of vision and hearing (Lentz_2010). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

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

Jul 29, 2021

- -

USH1C-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2024

The USH1C c.216G>A is a noncoding alteration. This variant is, however, predicted to strengthen a cryptic donor splice site (Alamut Visual Plus v1.6.1). This variant has been reported in the homozygous or compound heterozygous state in individuals with Usher syndrome and has been described as a founder variant in the Acadian population (Bitner-Glindzicz et al. 2000. PubMed ID: 10973248; Roux et al. 2011. PubMed ID: 21436283; Ebermann et al. 2007. PubMed ID: 17407589; Wafa et al. 2020. PubMed ID: 33089500). A functional study using RT-PCR found that this variant produces a shortened transcript, confirming the splicing prediction algorithms (Bitner-Glindzicz et al. 2000. PubMed ID: 10973248). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

The c.216G>A variant in USH1C has been reported in the homozygous or compound he terozygous state in at least 70 individuals with Usher syndrome (Roux 2011, Bitn er-Glindzicz 2000, DeAngelis 2001, Ebermann 2007, Lentz 2007, Lentz 2005, Lentz 2010, Ouyang 2003, Savas 2002, Zwaenepoel 2001). The variant has been shown to c reate a cryptic splice site and produce a 35-bp deletion in the RNA transcript i n lymphoblasts. This 35-bp deletion leads to a frameshift and premature terminat ion codon 189 bases downstream. In summary, this variant meets criteria to be cl assified as pathogenic for autosomal recessive Usher syndrome. -

Usher syndrome type 1

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.66

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.66

Position offset: 3

DS_DL_spliceai

0.64

Position offset: -32

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