ClinVar Genomic variation as it relates to human health
NM_153676.4(USH1C):c.1823C>G (p.Pro608Arg)
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); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_153676.4(USH1C):c.1823C>G (p.Pro608Arg)
Variation ID: 5148 Accession: VCV000005148.23
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.1 11: 17509546 (GRCh38) [ NCBI UCSC ] 11: 17531093 (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 25, 2015 Feb 14, 2024 Oct 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_153676.4:c.1823C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_710142.1:p.Pro608Arg missense NM_005709.4:c.1285-7566C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001297764.2:c.1228-7566C>G intron variant NC_000011.10:g.17509546G>C NC_000011.9:g.17531093G>C NG_011883.2:g.39871C>G - Protein change
- P608R
- Other names
- R608P
- Canonical SPDI
- NC_000011.10:17509545:G:C
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00068
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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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Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2002 | RCV000005455.4 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 6, 2015 | RCV000041259.7 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Oct 11, 2023 | RCV000755427.14 | |
Uncertain significance (2) |
criteria provided, single submitter
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Oct 8, 2021 | RCV001276292.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 21, 2021 | RCV001797045.1 |
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
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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
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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
(May 25, 2018)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605534.2
First in ClinVar: May 29, 2016 Last updated: Feb 17, 2019 |
Comment:
The p.Pro608Arg variant (rs41282932) has been identified in a homozygous state in a single induvial with non-syndromic hearing loss (Ouyang 2002). However it has been … (more)
The p.Pro608Arg variant (rs41282932) has been identified in a homozygous state in a single induvial with non-syndromic hearing loss (Ouyang 2002). However it has been identified in several other cases with an alternate molecular basis for hearing loss, suggesting that it is not a causative variant (Cremers 2007, and Vona 2014). The p.Pro608Arg variant has also been reported to ClinVar (Variation ID: 5148). This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.06 percent (identified on 8 out of 12,984 chromosomes) and is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.05 percent (identified on 124 out of 267,276 chromosomes). The proline at position 608 is weakly conserved (considering 12 species) (Alamut v.2.8.1) and computational analyses of the effects of the p.Pro608Arg variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Pro608Arg variant with certainty. (less)
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Likely benign
(Feb 06, 2015)
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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: SCV000064950.6
First in ClinVar: May 03, 2013 Last updated: Feb 17, 2019 |
Comment:
p.Pro608Arg in exon 18 of USH1C: This variant has been previously reported in 3 individuals with Usher syndrome or hearing loss and 2 individuals by … (more)
p.Pro608Arg in exon 18 of USH1C: This variant has been previously reported in 3 individuals with Usher syndrome or hearing loss and 2 individuals by our laborat ory; 3 of whom have another genetic etiology to explain their hearing loss (Crem ers 2007, Vera 2014, LMM unpublished data). This variant has also been identifie d in 0.1% (51/60306) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs41282932). In summary, the prese nce of this variant in 3 individuals with another etiology for hearing loss and its frequency in the general population suggest that it is likely benign. (less)
Number of individuals with the variant: 3
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Uncertain significance
(Jun 21, 2021)
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criteria provided, single submitter
Method: case-control
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Meniere disease
Affected status: yes
Allele origin:
inherited
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Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO)
Accession: SCV001738474.1
First in ClinVar: Dec 24, 2021 Last updated: Dec 24, 2021 |
Comment:
Digenic inheritance along with NM_000260.4:c.6247G>A(MYO7A)
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Uncertain significance
(Aug 24, 2021)
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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: SCV001873907.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
Observed as a heterozygous variant in patients with hearing loss who harbored variants in other hearing loss-related genes (Cremers FP et al., 2007; Vona B … (more)
Observed as a heterozygous variant in patients with hearing loss who harbored variants in other hearing loss-related genes (Cremers FP et al., 2007; Vona B et al., 2014; Nonose RW et al., 2018; Roman-Naranjo P et al., 2021); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 16963483, 12136232, 34391192, 30245029, 29739340, 24875298) (less)
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Uncertain significance
(Oct 08, 2021)
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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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Myriad Genetics, Inc.
Accession: SCV002060018.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_005709.3(USH1C):c.1285-7566C>G is an intronic variant classified as a variant of uncertain significance in the context of USH1C-related disorders. c.1285-7566C>G has been observed in cases with … (more)
NM_005709.3(USH1C):c.1285-7566C>G is an intronic variant classified as a variant of uncertain significance in the context of USH1C-related disorders. c.1285-7566C>G has been observed in cases with relevant disease (PMID: 12136232, 29739340, 16963483, 24875298). Functional assessments of this variant are not available in the literature. c.1285-7566C>G has been observed in population frequency databases (gnomAD: NFE 0.08%). In summary, there is insufficient evidence to classify NM_005709.3(USH1C):c.1285-7566C>G as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
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Likely benign
(Oct 11, 2023)
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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: SCV003255845.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
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Pathogenic
(Jul 01, 2002)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AUTOSOMAL RECESSIVE 18A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000025637.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 29, 2019 |
Comment on evidence:
In 1 of 32 Chinese multiplex families with nonsyndromic recessive deafness without retinitis pigmentosa (DFNB18A; 602092), Ouyang et al. (2002) found a C-to-G transversion in … (more)
In 1 of 32 Chinese multiplex families with nonsyndromic recessive deafness without retinitis pigmentosa (DFNB18A; 602092), Ouyang et al. (2002) found a C-to-G transversion in the alternatively spliced exon D of the USH1C gene, predicting an arg608-to-pro (R608P) substitution in the proline-, serine-, and threonine-rich region of harmonin. (less)
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Uncertain significance
(Apr 11, 2020)
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no assertion criteria provided
Method: clinical testing
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Usher syndrome type 1C
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001462402.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Mutation analysis of SLC26A4 (Pendrin) gene in a Brazilian sample of hearing-impaired subjects. | Nonose RW | BMC medical genetics | 2018 | PMID: 29739340 |
Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations. | Vona B | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24875298 |
Development of a genotyping microarray for Usher syndrome. | Cremers FP | Journal of medical genetics | 2007 | PMID: 16963483 |
Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness. | Ouyang XM | Human genetics | 2002 | PMID: 12136232 |
Text-mined citations for rs41282932 ...
HelpRecord last updated Feb 20, 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.