NM_005982.4(SIX1):c.373G>A (p.Glu125Lys) AND Autosomal dominant nonsyndromic hearing loss 23

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: May 22, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000190433.4

Allele description [Variation Report for NM_005982.4(SIX1):c.373G>A (p.Glu125Lys)]

NM_005982.4(SIX1):c.373G>A (p.Glu125Lys)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

14q23.1

Genomic location:

Preferred name:

NM_005982.4(SIX1):c.373G>A (p.Glu125Lys)

HGVS:

NC_000014.9:g.60648817C>T
NG_008231.1:g.5621G>A
NG_129185.1:g.777C>T
NG_129186.1:g.155C>T
NM_005982.4:c.373G>AMANE SELECT
NP_005973.1:p.Glu125Lys
NC_000014.8:g.61115535C>T
NM_005982.3:c.373G>A

Protein change:

E125K; GLU125LYS

Links:

OMIM: 601205.0005; dbSNP: rs797044960

NCBI 1000 Genomes Browser:

rs797044960

Molecular consequence:

NM_005982.4:c.373G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Autosomal dominant nonsyndromic hearing loss 23
Synonyms:: Deafness, autosomal dominant 23
Identifiers:: MONDO: MONDO:0011519; MedGen: C1854594; Orphanet: 90635; OMIM: 605192

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000244273	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 2011)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002521893	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 22, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21700001, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000244273

OMIM

no assertion criteria provided

Pathogenic
(Sep 1, 2011)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002521893

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 22, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

A novel dominant mutation in SIX1, affecting a highly conserved residue, result in only auditory defects in humans.

Mosrati MA, Hammami B, Rebeh IB, Ayadi L, Dhouib L, Ben Mahfoudh K, Hakim B, Charfeddine I, Mnif J, Ghorbel A, Masmoudi S.

Eur J Med Genet. 2011 Sep-Oct;54(5):e484-8. doi: 10.1016/j.ejmg.2011.06.001. Epub 2011 Jun 15.

PubMed [citation]

PMID:: 21700001

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000244273.2

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

Description

By direct sequencing of the SIX1 gene in an affected member of a Tunisian family with autosomal dominant hearing impairment and preauricular pits mapping to 14q23, Mosrati et al. (2011) identified a heterozygous c.373G-A transition, predicted to result in a glu125-to-lys (E125K) substitution at a conserved residue. Segregation of the variant with the phenotype was confirmed by PCR restriction fragment length polymorphism. The glu125 residue is located in the N-terminal arm and is likely to affect DNA binding.

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

From 3billion, SCV002521893.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.79; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SIX1 related disorder (ClinVar ID: VCV000208361 / PMID: 21700001).The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 21700001). 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

Last Updated: Mar 5, 2024

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