ClinVar Genomic variation as it relates to human health
NM_153676.4(USH1C):c.2167C>T (p.Gln723Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(4); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_153676.4(USH1C):c.2167C>T (p.Gln723Ter)
Variation ID: 47990 Accession: VCV000047990.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.1 11: 17504664 (GRCh38) [ NCBI UCSC ] 11: 17526211 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 5, 2015 Feb 14, 2024 Jul 18, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_153676.4:c.2167C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_710142.1:p.Gln723Ter nonsense NM_005709.4:c.1285-2684C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001297764.2:c.1228-2684C>T intron variant NC_000011.10:g.17504664G>A NC_000011.9:g.17526211G>A NG_011883.2:g.44753C>T - Protein change
- Q723*
- Other names
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- Canonical SPDI
- NC_000011.10:17504663:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00100 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00015
Exome Aggregation Consortium (ExAC) 0.00023
The Genome Aggregation Database (gnomAD) 0.00068
Trans-Omics for Precision Medicine (TOPMed) 0.00077
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092
1000 Genomes Project 0.00100
1000 Genomes Project 30x 0.00141
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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USH1C | - | - |
GRCh38 GRCh37 |
1360 | 1384 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (2) |
no assertion criteria provided
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Apr 7, 2019 | RCV000041266.11 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 30, 2022 | RCV000211746.6 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jul 18, 2022 | RCV000725879.14 | |
Uncertain significance (2) |
criteria provided, single submitter
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- | RCV000984230.3 | |
no classifications from unflagged records (1) |
no classifications from unflagged records
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Dec 7, 2023 | RCV001004552.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Dec 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000064957.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 3
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Uncertain significance
(Jun 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002556279.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
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. … (more)
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. (less)
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Uncertain significance
(Jul 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002552684.2
First in ClinVar: Jul 29, 2022 Last updated: Mar 04, 2023 |
Comment:
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; … (more)
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) (less)
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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Usher syndrome type 1C
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV002583280.2
First in ClinVar: Oct 15, 2022 Last updated: Mar 18, 2023 |
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Benign
(Dec 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001065968.3
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Uncertain significance
(Apr 07, 2019)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 18A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132307.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Uncertain significance
(Apr 07, 2019)
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no assertion criteria provided
Method: clinical testing
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Usher syndrome type 1C
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132306.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Likely pathogenic
(Feb 20, 2015)
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Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Deafness, autosomal recessive 18A
Affected status: no
Allele origin:
germline
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000238426.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Apr 08, 2016)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000340206.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(-)
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Flagged submission
flagged submission
Method: clinical testing
Reason: New submission from submitter that appears to have been intended to update this older submission
Source: ClinGen
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Usher syndrome type 1
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163631.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Curating Clinically Relevant Transcripts for the Interpretation of Sequence Variants. | DiStefano MT | The Journal of molecular diagnostics : JMD | 2018 | PMID: 30096381 |
Utility and limitations of exome sequencing as a genetic diagnostic tool for children with hearing loss. | Sheppard S | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29907799 |
Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness. | Ouyang XM | Human genetics | 2002 | PMID: 12136232 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH1C | - | - | - | - |
Text-mined citations for rs146451547 ...
HelpRecord last updated Mar 11, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.