rs146451547

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PVS1BS1_Supporting

The NM_153676.4(USH1C):c.2167C>T(p.Gln723*) 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:8B:1

Conservation

PhyloP100: 3.72

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000766 (112/1461870) while in subpopulation AFR AF = 0.00317 (106/33478). AF 95% confidence interval is 0.00268. There are 0 homozygotes in GnomAdExome4. There are 52 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH1C	NM_153676.4 link	c.2167C>T	p.Gln723*	stop_gained	Exon 20 of 27	ENST00000005226.12	NP_710142.1	Q9Y6N9-5
USH1C	NM_005709.4 link	c.1285-2684C>T		intron_variant	Intron 15 of 20	ENST00000318024.9	NP_005700.2	Q9Y6N9-1A0A0S2Z4U9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH1C	ENST00000005226.12 link	c.2167C>T	p.Gln723*	stop_gained	Exon 20 of 27	5	NM_153676.4	ENSP00000005226.7		Q9Y6N9-5
USH1C	ENST00000318024.9 link	c.1285-2684C>T		intron_variant	Intron 15 of 20	1	NM_005709.4	ENSP00000317018.4		Q9Y6N9-1

Frequencies

GnomAD3 genomes

AF:

0.000638

AC:

AN:

151958

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000151

AC:

AN:

251424

AF XY:

0.000140

show subpopulations

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 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.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00317

AC:

106

AN:

33478

Gnomad4 AMR exome

AF:

0.0000447

AC:

AN:

44722

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26134

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0000116

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53410

Gnomad4 NFE exome

AF:

8.99e-7

AC:

AN:

1112006

Gnomad4 Remaining exome

AF:

0.0000331

AC:

AN:

60396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000638

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00227

AC:

0.00226735

AN:

0.00226735

Gnomad4 AMR

AF:

0.000131

AC:

0.000130839

AN:

0.000130839

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000147

AC:

0.0000147063

AN:

0.0000147063

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000230

Hom.:

Bravo

AF:

0.000767

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1Benign:1

Jul 18, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Dec 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2016

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 1C

Uncertain:3

Apr 07, 2019

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 18A

Pathogenic:1Uncertain:1

Apr 07, 2019

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 20, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:research

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. -

not specified

Uncertain:2

Dec 13, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: USH1C c.1285-2684C>T is located at a position not widely known to affect splicing. Consensus agreement among computation 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 significantly higher than estimated for a pathogenic variant in USH1C causing Usher Syndrome (0.00015 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29907799, 30096381). ClinVar contains an entry for this variant (Variation ID: 47990). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Usher syndrome type 1

Uncertain:1

Sep 29, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1285-2684C>T variant in the USH1C gene (NM_005709.4), also known as c.2167C>T (p.Q723*) in NM_153676.4, has been reported in a heterozygous state with no second variant in an individual with mild sensorineural hearing loss (PMID: 29907799). At this time, there is no definitive correlation between the NM_153676.4 isoform and Usher syndrome, so we have classified this variant as uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Benign

0.46

Vest4

0.71

GERP RS

5.6

Mutation Taster

=7/193

disease causing (ClinVar)

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

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