rs1207247951

Positions:

• chr11-17517464-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.47

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

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	c.1220del	p.Gly407GlufsTer58	frameshift_variant	15/21	ENST00000318024.9	NP_005700.2
USH1C	NM_153676.4	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	c.1220del	p.Gly407GlufsTer58	frameshift_variant	15/21	1	NM_005709.4	ENSP00000317018	P1
USH1C	ENST00000005226.12	c.1211-1175del		intron_variant		5	NM_153676.4	ENSP00000005226

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1440504 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

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

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

Other links and lift over

dbSNP: rs1207247951; hg19: chr11-17539011;