rs146451547

Positions:

• chr11-17504664-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_153676.4(USH1C):​c.2167C>T​(p.Gln723Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000129 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: USH1C NM_153676.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:7 B:1
• Conservation: PhyloP100: 3.72

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 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH1C	NM_153676.4	c.2167C>T	p.Gln723Ter	stop_gained	20/27	ENST00000005226.12	NP_710142.1
USH1C	NM_005709.4	c.1285-2684C>T		intron_variant		ENST00000318024.9	NP_005700.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12	c.2167C>T	p.Gln723Ter	stop_gained	20/27	5	NM_153676.4	ENSP00000005226
USH1C	ENST00000318024.9	c.1285-2684C>T		intron_variant		1	NM_005709.4	ENSP00000317018	P1

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 97 AN: 151958 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000151 AC: 38 AN: 251424 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135886

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000766 AC: 112 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000715 AC XY: 52 AN XY: 727240

Gnomad4 AFR exome AF: 0.00317

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000638 AC: 97 AN: 152074 Hom.: 0 Cov.: 33 AF XY: 0.000632 AC XY: 47 AN XY: 74336

Gnomad4 AFR AF: 0.00227

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000767

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Benign:1

Likely pathogenic, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Apr 08, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Observed in apparent homozygous state in a patient with nonsyndromic hearing loss at an outside laboratory and not observed in homozygous state in controls; This variant is associated with the following publications: (PMID: 29907799, 31053783, 12136232, 30096381) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2021	- -

Usher syndrome type 1C Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	Apr 07, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Autosomal recessive nonsyndromic hearing loss 18A Pathogenic:1 Uncertain:1

Likely pathogenic, flagged submission	research	Division of Human Genetics, Children's Hospital of Philadelphia	Feb 20, 2015	This heterozygous variant (c.2167C>T; p.Gln723X) variant has not been previously reported in the literature but has been reported in the ClinVar database as likely pathogenic by the Laboratory for Molecular Medicine in two families. This variant is predicted to result in a premature protein truncation in only one isoform (NM_153676.3). Missense mutations have been reported in exons specific to this isoform in patients with non-syndromic hearing loss, suggesting that alterations affecting only this isoform may result in a clinical phenotype (PMID: 12136232). This isoform is known to be expressed in the inner ear but not in the eye, which may explain the lack of an eye phenotype in the reported patients. Because the mode of inheritance for this condition does not match the observed inheritance of the disorder in the family this variant was not considered to be causative of the patient’s clinical presentation of hearing loss. -
Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	Apr 07, 2019	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 13, 2018	The p.Gln723X variant in USH1C has been previously identified in the homozygous state in one African American individual with hearing loss with no reported eye findings (LMM unpublished data). This variant has been reported in ClinVar (Vari ant ID: 47990). However, it has also been identified in 0.25% (59/24002) African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org). This variant leads to a premature stop codon at position 723. Howeve r, the p.Gln723X variant is located in exon 20 of an alternatively spiced isofor m. This splice isoform has been reported to be expressed in the inner ear and n ot in the retina based upon studies in mice (Ouyang 2002). However, there is ins ufficient evidence in humans to support whether variants in the exons unique to this isoform would result in hearing loss or Usher syndrome. In addition to the p.Gln723X variant, there is a second putative loss of function variant that is a lso unique to this transcript that is present at a high frequency in the general population and as such, it is not clear whether variants in this exon are disea se causing (DiStefano 2018). In summary, due to the uncertainty whether variants affecting the exons specific to the transcript in which p.Gln723X lies, the cli nical significance of the p.Gln723X variant is uncertain. ACMG/AMP criteria appl ied: PVS1_Moderate, BS1_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 30, 2022	Variant summary: USH1C c.1285-2684C>T is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00015 in 251424 control chromosomes, predominantly at a frequency of 0.0023 within the African or African-American subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in USH1C causing Usher Syndrome (0.0023 vs 0.0029), allowing no conclusion about variant significance. The variant results in a premature termination codon in an alternate transcript (NM_153676.3: c.2167C>T, p.Gln723X). In this alternate transcript, the variant is located within exon 20 which Di Stefano et al (2018) determined to be a 'distinct exon of uncertain significance'. Transcripts containing alternatively spliced exons were found to be expressed in the inner ear, but not in the eye (PMID 12136232). c.2167C>T has been reported in the literature in a heterozygous individual affected with mild bilateral sensorineural hearing Loss (Sheppard_2018), while it was also reported by a ClinVar submitter in a homozygous African American individual with hearing loss but no reported eye findings (SCV000064957.6). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=1), VUS (n=2) and likely pathogenic (n=2). Based on the evidence outlined above, and due to the uncertainty about the clinical significance of the unique exon where p.Gln723X lies within the alternate transcript, the variant was classified as uncertain significance. -

Usher syndrome type 1 Pathogenic:1

Pathogenic, flagged submission

clinical testing

Baylor Genetics

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	55
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Benign	0.46	N
MutationTaster	Benign	1.0	A;D;D;D
Vest4		0.71
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.38		Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs146451547; hg19: chr11-17526211;