Variant chr11-17517464-TC-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_005709.4(USH1C):c.1220del(p.Gly407GlufsTer58) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

USH1C
NM_005709.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.47

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:

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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 11-17517464-TC-T is Pathogenic according to our data. Variant chr11-17517464-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 555064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17517464-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_005709.4 linkuse as main transcript	c.1220del	p.Gly407GlufsTer58	frameshift_variant	15/21	ENST00000318024.9	NP_005700.2
USH1C	NM_153676.4 linkuse as main transcript	c.1211-1175del		intron_variant		ENST00000005226.12	NP_710142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000318024.9 linkuse as main transcript	c.1220del	p.Gly407GlufsTer58	frameshift_variant	15/21	1	NM_005709.4	ENSP00000317018	P1	Q9Y6N9-1
USH1C	ENST00000005226.12 linkuse as main transcript	c.1211-1175del		intron_variant		5	NM_153676.4	ENSP00000005226		Q9Y6N9-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1440504

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714100

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Usher syndrome type 1C

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 12, 2020	- -

Autosomal recessive nonsyndromic hearing loss 18A

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 14, 2023

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Nov 15, 2017

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change creates a premature translational stop signal (p.Gly407Glufs*58) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 23251578, 29490346). ClinVar contains an entry for this variant (Variation ID: 555064). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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