rs1554960388

Variant names:

• chr11-17520933-G-GT
• rs1554960388
• NM_153676.4:c.1146dupA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_153676.4(USH1C):​c.1146dupA​(p.Gln383ThrfsTer6) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: USH1C NM_153676.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.413

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 11-17520933-G-GT is Pathogenic according to our data. Variant chr11-17520933-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555436.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.1146dupA	p.Gln383ThrfsTer6	frameshift_variant	Exon 14 of 27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1146dupA	p.Gln383ThrfsTer6	frameshift_variant	Exon 14 of 21	ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.1146dupA	p.Gln383ThrfsTer6	frameshift_variant	Exon 14 of 27	5	NM_153676.4	ENSP00000005226.7
USH1C	ENST00000318024.9	c.1146dupA	p.Gln383ThrfsTer6	frameshift_variant	Exon 14 of 21	1	NM_005709.4	ENSP00000317018.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461830 Hom.: 0 Cov.: 48 AF XY: 0.00 AC XY: 0 AN XY: 727220

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: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jan 15, 2025

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27957503) -

Sep 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.Gln383Thrfs*6) 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 type 1C (PMID: 27957503). ClinVar contains an entry for this variant (Variation ID: 555436). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 18A Pathogenic:1

Mar 05, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

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

Dec 05, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1554960388; hg19: chr11-17542480;