ClinVar Genomic variation as it relates to human health
NM_005982.4(SIX1):c.397_399del (p.Glu133del)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005982.4(SIX1):c.397_399del (p.Glu133del)
Variation ID: 8310 Accession: VCV000008310.11
- Type and length
-
Deletion, 3 bp
- Location
-
Cytogenetic: 14q23.1 14: 60648791-60648793 (GRCh38) [ NCBI UCSC ] 14: 61115509-61115511 (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 Feb 28, 2024 Aug 4, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_005982.4:c.397_399del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005973.1:p.Glu133del inframe deletion NM_005982.3:c.397_399del NC_000014.9:g.60648793_60648795del NC_000014.8:g.61115511_61115513del NG_008231.1:g.5645_5647del - Protein change
- E133del
- Other names
- E133delE
- Canonical SPDI
- NC_000014.9:60648790:CTCCT:CT
-
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.
-
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. |
|||
SIX1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
171 | 220 |
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 (1) |
no assertion criteria provided
|
May 25, 2004 | RCV000008808.3 | |
Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
May 5, 2023 | RCV000020636.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 4, 2023 | RCV002512920.2 | |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 21, 2023 | RCV003162220.1 |
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
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Aug 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Branchiootic syndrome 3
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579462.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
|
|
Pathogenic
(Mar 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003915023.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
Comment:
Functional studies demonstrate a damaging effect; variant results in diminished DNA binding and decreased lacZ activity (Ruf RG et al., 2004; Patrick AN et al., … (more)
Functional studies demonstrate a damaging effect; variant results in diminished DNA binding and decreased lacZ activity (Ruf RG et al., 2004; Patrick AN et al., 2009); In-frame deletion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15141091, 19497856, 33105617, 31595699) (less)
|
|
Likely pathogenic
(May 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Branchiootic syndrome 3
Affected status: yes
Allele origin:
germline
|
Laboratory of Otorhinolaryngology, Head and Neck Surgery, Seoul National University Hospital
Accession: SCV003927059.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Sex: female
|
|
Likely pathogenic
(Aug 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nonsyndromic hearing loss 23
Branchiootic syndrome 3
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003442890.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects SIX1 function (PMID: 15141091, 19497856, 23435380). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 8310). This variant is also known as delE133. This variant has been observed in individuals with branchiootorenal spectrum conditions and/or early onset deafness (PMID: 15141091, 36633841; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.397_399del, results in the deletion of 1 amino acid(s) of the SIX1 protein (p.Glu133del), but otherwise preserves the integrity of the reading frame. (less)
|
|
Likely pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Branchiootic syndrome 3
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573347.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region is predicted to change the length of the … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region is predicted to change the length of the protein and disrupt normal protein function. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19497856). The variant has been reported to be associated with SIX1-related disorder (ClinVar ID: VCV000008310 / PMID: 15141091). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present)
|
|
Likely pathogenic
(Feb 28, 2023)
|
criteria provided, single submitter
Method: research
|
Branchiootic syndrome 3
Affected status: yes
Allele origin:
maternal
|
King Laboratory, University of Washington
Accession: SCV003844145.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
This variant was found in heterozygosity in a patient and their mother, both with bilateral sensorineural hearing loss of onset <18 years, in a study … (more)
This variant was found in heterozygosity in a patient and their mother, both with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). At the time of recruitment, both patients had preauricular ear pits, but had no other signs associated with branchio-oto-renal syndrome. This family has no other history of hearing loss outside of the proband and their mother. This variant is a three base pair deletion that results in the deletion of the glutamine residue at position 133 of the SIX1 protein. As of January 2023, this variant has been reported to ClinVar as pathogenic/likely pathogenic and is not found on gnomAD. Based on co-segregation with the phenotype in the family and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. (less)
|
|
Pathogenic
(May 25, 2004)
|
no assertion criteria provided
Method: literature only
|
DEAFNESS, AUTOSOMAL DOMINANT 23
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029018.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 08, 2015 |
Comment on evidence:
In a member of a family previously reported by Salam et al. (2000) with DFNA23 (605192), Ruf et al. (2004) identified heterozygosity for a 3-bp … (more)
In a member of a family previously reported by Salam et al. (2000) with DFNA23 (605192), Ruf et al. (2004) identified heterozygosity for a 3-bp deletion (397delGGA) in the SIX1 gene, resulting in the deletion of glutamic acid at position 133. In addition to deafness, the patient had a solitary left hypodysplastic kidney with vesicoureteral reflux and progressive renal failure, suggesting that this family may have BOR/BO syndrome. (less)
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Branchiootic syndrome 3
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000041157.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022 |
|
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 |
---|---|---|---|---|
Association of Genetic Diagnoses for Childhood-Onset Hearing Loss With Cochlear Implant Outcomes. | Carlson RJ | JAMA otolaryngology-- head & neck surgery | 2023 | PMID: 36633841 |
Branchiootorenal Spectrum Disorder. | Adam MP | - | 2018 | PMID: 20301554 |
Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome. | Patrick AN | Nature structural & molecular biology | 2013 | PMID: 23435380 |
Biochemical and functional characterization of six SIX1 Branchio-oto-renal syndrome mutations. | Patrick AN | The Journal of biological chemistry | 2009 | PMID: 19497856 |
SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. | Ruf RG | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15141091 |
A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred. | Salam AA | American journal of human genetics | 2000 | PMID: 10777717 |
Text-mined citations for rs80356460 ...
HelpRecord last updated Mar 05, 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.