This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the DFNB59 protein (p.Arg183Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 16804542, 17373699, 27344577). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1297). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DFNB59 function (PMID: 16804542). 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.
ClinVar Genomic variation as it relates to human health
NM_001042702.5(PJVK):c.547C>T (p.Arg183Trp)
Germline
Classification
Help
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.
(6)
Help
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.
Pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001042702.5(PJVK):c.547C>T (p.Arg183Trp)
Variation ID: 1297 Accession: VCV000001297.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q31.2 2: 178456149 (GRCh38) [ NCBI UCSC ] 2: 179320876 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 4, 2013 Nov 17, 2024 Sep 16, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001042702.5:c.547C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001036167.1:p.Arg183Trp missense NM_001042702.3:c.547C>T NM_001353775.2:c.556C>T NP_001340704.1:p.Arg186Trp missense NM_001353776.2:c.652C>T NP_001340705.1:p.Arg218Trp missense NM_001353777.1:c.70C>T NP_001340706.1:p.Arg24Trp missense NM_001353778.2:c.70C>T NP_001340707.1:p.Arg24Trp missense NM_001369912.1:c.547C>T NP_001356841.1:p.Arg183Trp missense NC_000002.12:g.178456149C>T NC_000002.11:g.179320876C>T NG_009053.1:g.83G>A NG_012186.1:g.9714C>T Q0ZLH3:p.Arg183Trp - Protein change
- R183W, R186W, R218W, R24W
- Other names
- -
- Canonical SPDI
- NC_000002.12:178456148:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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
Help
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. |
|||
| PJVK | - | - |
GRCh38 GRCh37 |
252 | 293 | |
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
Sep 16, 2024 | RCV000001360.5 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 6, 2024 | RCV001268818.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 10, 2021 | RCV001813933.2 |
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
Help
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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|---|---|---|---|---|---|
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Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448009.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hearing impairment (present) , Sensorineural hearing loss disorder (present) , Abnormal nasal septum morphology (present) , Hypothyroidism (present)
Sex: male
|
|
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Pathogenic
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003524828.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the DFNB59 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the DFNB59 protein (p.Arg183Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 16804542, 17373699, 27344577). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1297). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DFNB59 function (PMID: 16804542). 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. (less)
|
|
|
Pathogenic
(Feb 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003933377.2
First in ClinVar: Jun 24, 2023 Last updated: Sep 29, 2024 |
Comment:
Published functional studies demonstrate a damaging effect resulting in conduction anomalies and reduced amplitudes of ABR waves compared to wildtype (PMID: 16804542); Not observed at … (more)
Published functional studies demonstrate a damaging effect resulting in conduction anomalies and reduced amplitudes of ABR waves compared to wildtype (PMID: 16804542); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 27344577, 30582396, 17373699, 34426522, 35052489, 16804542, 35982127) (less)
|
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Pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Ear malformation
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755175.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
|
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Pathogenic
(Sep 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive nonsyndromic hearing loss 59
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005394293.1
First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024 |
Comment:
Variant summary: PJVK c.547C>T (p.Arg183Trp) results in a non-conservative amino acid change located in the Gasdermin, pore forming domain of the encoded protein sequence. Four … (more)
Variant summary: PJVK c.547C>T (p.Arg183Trp) results in a non-conservative amino acid change located in the Gasdermin, pore forming domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. Three predict the variant creates a cryptic 5' donor site. The variant allele was found at a frequency of 7.1e-06 in 280146 control chromosomes. c.547C>T has been reported in the literature in multiple individuals affected with Auditory neuropathy (example: Delmaghani_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental studies that this missense change affects protein function (example: Delmaghani_2006). The following publication has been ascertained in the context of this evaluation (PMID: 16804542).ClinVar contains an entry for this variant (Variation ID: 1297). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jul 01, 2007)
|
no assertion criteria provided
Method: literature only
|
DEAFNESS, AUTOSOMAL RECESSIVE 59
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000021510.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 16, 2020 |
Comment on evidence:
In a consanguineous Iranian family with multiple members affected by nonsyndromic deafness due to a neuronal defect (DFNB59; 610220) Delmaghani et al. (2006) found homozygosity … (more)
In a consanguineous Iranian family with multiple members affected by nonsyndromic deafness due to a neuronal defect (DFNB59; 610220) Delmaghani et al. (2006) found homozygosity for an arg183-to-trp (R183W) substitution in pejvakin that arose from a 547C-T transition in exon 4 of the gene. The same mutation was found in 2 other Iranian families cosegregating a neuronal type of autosomal recessive nonsyndromic deafness. Collin et al. (2007) identified homozygosity for the R183W mutation in 1 of 67 unrelated consanguineous Turkish families with autosomal recessive nonsyndromic hearing loss. Haplotype analysis did not suggest a founder effect for the Turkish and Iranian families with the mutation. In contrast to the Iranian patients reported by Delmaghani et al. (2006), Collin et al. (2007) found that transiently evoked otoacoustic emissions (OAE) were absent in the Turkish patients, indicating altered outer hair cell function. (less)
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect resulting in conduction anomalies and reduced amplitudes of ABR waves compared to wildtype (PMID: 16804542); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 27344577, 30582396, 17373699, 34426522, 35052489, 16804542, 35982127)
Comment:
Variant summary: PJVK c.547C>T (p.Arg183Trp) results in a non-conservative amino acid change located in the Gasdermin, pore forming domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. Three predict the variant creates a cryptic 5' donor site. The variant allele was found at a frequency of 7.1e-06 in 280146 control chromosomes. c.547C>T has been reported in the literature in multiple individuals affected with Auditory neuropathy (example: Delmaghani_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental studies that this missense change affects protein function (example: Delmaghani_2006). The following publication has been ascertained in the context of this evaluation (PMID: 16804542).ClinVar contains an entry for this variant (Variation ID: 1297). Based on the evidence outlined above, the variant was classified as pathogenic.
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. |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the DFNB59 protein (p.Arg183Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 16804542, 17373699, 27344577). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1297). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DFNB59 function (PMID: 16804542). 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.
Comment:
Published functional studies demonstrate a damaging effect resulting in conduction anomalies and reduced amplitudes of ABR waves compared to wildtype (PMID: 16804542); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 27344577, 30582396, 17373699, 34426522, 35052489, 16804542, 35982127)
Comment:
Variant summary: PJVK c.547C>T (p.Arg183Trp) results in a non-conservative amino acid change located in the Gasdermin, pore forming domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. Three predict the variant creates a cryptic 5' donor site. The variant allele was found at a frequency of 7.1e-06 in 280146 control chromosomes. c.547C>T has been reported in the literature in multiple individuals affected with Auditory neuropathy (example: Delmaghani_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental studies that this missense change affects protein function (example: Delmaghani_2006). The following publication has been ascertained in the context of this evaluation (PMID: 16804542).ClinVar contains an entry for this variant (Variation ID: 1297). Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Spectrum of DNA variants for non-syndromic deafness in a large cohort from multiple continents. | Yan D | Human genetics | 2016 | PMID: 27344577 |
| Involvement of DFNB59 mutations in autosomal recessive nonsyndromic hearing impairment. | Collin RW | Human mutation | 2007 | PMID: 17373699 |
| Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. | Delmaghani S | Nature genetics | 2006 | PMID: 16804542 |
Text-mined citations for rs111706634 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 19, 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.