NM_005982.4(SIX1):c.397_399del (p.Glu133del) AND Branchiootic syndrome 3

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: May 5, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000020636.9

Allele description [Variation Report for NM_005982.4(SIX1):c.397_399del (p.Glu133del)]

NM_005982.4(SIX1):c.397_399del (p.Glu133del)

Gene:

SIX1:SIX homeobox 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

14q23.1

Genomic location:

Preferred name:

NM_005982.4(SIX1):c.397_399del (p.Glu133del)

Other names:

E133delE

HGVS:

NC_000014.9:g.60648793_60648795del
NG_008231.1:g.5645_5647del
NM_005982.4:c.397_399delMANE SELECT
NP_005973.1:p.Glu133del
NC_000014.8:g.61115509_61115511del
NC_000014.8:g.61115511_61115513del
NM_005982.2:c.397_399del
NM_005982.3:c.397_399del

Protein change:

E133del

Links:

OMIM: 601205.0003; dbSNP: rs80356460

NCBI 1000 Genomes Browser:

rs80356460

Molecular consequence:

NM_005982.4:c.397_399del - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

Name:: Branchiootic syndrome 3 (BOS3)
Synonyms:: BO SYNDROME 3
Identifiers:: MONDO: MONDO:0012025; MedGen: C1842124; OMIM: 608389

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000041157	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 10777717, 15141091
SCV002573347	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15141091, 19497856, 25741868
SCV002579462	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 16, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003844145	King Laboratory, University of Washington	criteria provided, single submitter (Li et al. (Genet Med. 2022))	Likely pathogenic (Feb 28, 2023)	maternal	research	PubMed (2) [See all records that cite these PMIDs] 36633841, 35802133
SCV003927059	Laboratory of Otorhinolaryngology, Head and Neck Surgery, Seoul National University Hospital	criteria provided, single submitter (ACMG AMP Guidelines)	Likely pathogenic (May 5, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred.

Salam AA, Häfner FM, Linder TE, Spillmann T, Schinzel AA, Leal SM.

Am J Hum Genet. 2000 Jun;66(6):1984-8. Epub 2000 Apr 24.

PubMed [citation]

PMID:: 10777717
PMCID:: PMC1378045

SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes.

Ruf RG, Xu PX, Silvius D, Otto EA, Beekmann F, Muerb UT, Kumar S, Neuhaus TJ, Kemper MJ, Raymond RM Jr, Brophy PD, Berkman J, Gattas M, Hyland V, Ruf EM, Schwartz C, Chang EH, Smith RJ, Stratakis CA, Weil D, Petit C, Hildebrandt F.

Proc Natl Acad Sci U S A. 2004 May 25;101(21):8090-5. Epub 2004 May 12.

PubMed [citation]

PMID:: 15141091
PMCID:: PMC419562

See all PubMed Citations (7)

Details of each submission

From GeneReviews, SCV000041157.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002573347.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002579462.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From King Laboratory, University of Washington, SCV003844145.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Otorhinolaryngology, Head and Neck Surgery, Seoul National University Hospital, SCV003927059.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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